A Hybrid Type 2 Effectiveness-Implementation Evaluation of HIV-1/HIV-2 Differential Testing and Risk Compensation among Lenacapavir PrEP Users in Kenya

Abstract Background: In February 2026, Kenya initiated a phased rollout of twice-yearly injectableLenacapavir (LEN) for HIV pre-exposure prophylaxis (PrEP) across 15 high-priority counties.However, LEN exhibits a critical pharmacological constraint, demonstrating an 11- to 25-foldreduction in potency against HIV-2 compared to HIV-1. In this low-prevalence landscape,standard clinical routines frequently fail to record specific HIV-2 results from primarydiscriminatory assays, a gap potentially exacerbated by PrEP-associated risk compensationacross sexual and injection practices. Objectives: The primary objective is to evaluate the dual impact of integrating routine HIV-1/2differential testing on clinical effectiveness and implementation success, while assessing theinfluence of risk compensation among Lenacapavir PrEP users in Kenya. Briefly, the specificobjectives are to: (1) determine the incidence and yield of HIV-1 and HIV-2 detections in alongitudinal cohort; (2) evaluate implementation outcomes (feasibility, adoption, and reach) at 3-month visits using the RE-AIM framework; (3) assess risk compensation by measuringlongitudinal changes in high-risk practices from initiation to 3-month follow-up ; and (4) identifybarriers and facilitators influencing testing integration, specifically provider failure todifferentiate strains using the TrinScreen. Methodology: This study employs a hybrid Type 2 effectiveness-implementation designutilizing a convergent parallel mixed-methods approach. A longitudinal cohort of HIV-negativeadults (N = 300) initiating LEN PrEP will be purposively sampled across high-burden clinics inNairobi, Homabay, and Kisumu. Quantitative data collection will occur at baseline (0 months)and follow-up (3 months) via TrinScreen screening and behavioral surveys, complemented byqualitative semi-structured interviews (n =20 - 40) with clients and providers. Quantitative datawill be analyzed using logistic regression to evaluate behavioral predictors of seroconversion,while qualitative data will undergo thematic analysis. Significance: By evaluating the diagnostic accuracy and Positive Predictive Value (PPV) of theTrinScreen’s discriminatory lines in a low-prevalence environment, this research mitigates therisk of diagnostic misclassification, preserving future therapeutic pathways for drug-resistantstrains. Furthermore, by quantifying compensatory behavioral shifts, this study provides criticalempirical evidence to the National Syndemic Diseases Control Council (NSDCC) and theMinistry of Health. These findings will directly inform national clinical guidelines and guide thescalable integration of differential testing within long-acting PrEP rollout infrastructuresglobally. Keywords: Lenacapavir, HIV-2 Surveillance, Hybrid Type 2 Design, Risk Compensation,TrinScreen, PrEP, Viral Capsid Variation.