LAI-PrEP Bridge Period Decision Support Tool v4.1.0: Code, Configuration, and Supplementary Materials

Published December 2025 | Code & Configuration Version 2.1.0 | Manuscript Version 4.1.0 Overview Long-acting injectable cabotegravir (LAI-CAB) and lenacapavir for HIV pre-exposure prophylaxis demonstrate >96% efficacy but face a critical implementation challenge: 47% of patients prescribed LAI-PrEP never receive their first injection during the "bridge period" between prescription and administration. This tool addresses this gap through systematic risk assessment and evidence-based intervention selection. Tool Components Core Algorithm (lai_prep_decision_tool_v2_1.py, 850 lines) Population-specific risk stratification Barrier impact quantification Intervention recommendation with mechanism diversity scoring External Configuration (lai_prep_config.json, 558 lines) 7 populations 13 barriers 21 evidence-based interventions with literature-derived effect sizes Comprehensive Test Suite (test_edge_cases.py, 18 scenarios) 100% pass rate Covers clinical edge cases, mathematical validation, mechanism diversity, data export, error handling Command-Line Interface (cli.py) Single patient assessment Batch processing Configuration validation Validation Scripts Progressive validation from 1K to 21.2M patients Documentation & Examples Installation guides, API reference, integration instructions Individual patient JSON template Batch CSV with 10 diverse scenarios Validation Results Progressive Scales Validated on 1K (functional), 1M (large-scale), 10M (ultra-large-scale), 21.2M patients (UNAIDS global target) Precision ±0.018 percentage point margin of error at 21.2M scale (policy-grade statistical precision) Unit Testing 100% pass rate (18/18 edge cases) Population Alignment All predictions within published clinical trial ranges Predicted Impact 81.6% relative improvement (baseline 23.96% → 43.50% with interventions) 4.1 million additional successful LAI-PrEP transitions globally ~100,000 HIV infections prevented annually (assuming 2–5% incidence, 96% efficacy) $40 billion in lifetime treatment costs saved Greatest benefits to PWID (+265%) and adolescents (+147%) Manuscript Supplements Companion Manuscript 1: Computational Validation Paper Title: Computational Validation of a Clinical Decision Support Algorithm for Long-Acting Injectable PrEP Bridge Period Navigation at UNAIDS Global Target Scale LAI Supplementary Files (5 total): S1: Machine-Readable Clinical Trial Evidence Detailed evidence summaries from HPTN 083, HPTN 084, PURPOSE-1, PURPOSE-2 Safety considerations and implications for bridge period design Islatravir clinical hold case study: Lessons learned for long-acting HIV prevention Development timeline, safety signal details, regulatory response Irreversibility principle and implications for pre-dosing assessment Comparison of safety monitoring standards for cabotegravir vs. lenacapavir Extrapolation from islatravir to bridge period protocol design Regulatory framework evolution post-islatravir (2021-present) Current best practices for bridge period safety assessment informed by islatravir experience Bridge period reframed as adaptive safety framework rather than obstacle S2: Complete Intervention Library 21 evidence-based interventions for bridge period navigation Effect size estimates from published literature Evidence strength ratings (Strong/Moderate/Emerging) Implementation complexity assessments Mechanism classifications and diversity scoring rules Methodological notes on effect calculation, barrier impact, target populations S3: AI Readiness Assessment Automation bias and complacency in healthcare AI systems Algorithmic bias recognition and mitigation strategies Human-in-the-loop safeguards for clinical decision support Transparency and accountability frameworks Regulatory and ethical considerations S4: Code Repository & Technical Documentation Python implementation (lai_prep_decision_tool_v2_1.py) Configuration file documentation (lai_prep_config.json) Test suite and validation protocols (test_edge_cases.py) GitHub repository structure and contributing guidelines API reference and deployment instructions S5: Additional Statistical Tables Convergence analysis across scales (1K to 21.2M patients) Sensitivity analyses (diminishing returns factor, success rate ceiling) Mechanism overlap penalty calculations Population-specific effect estimates and CIs Companion Manuscript 2: Implementation Review Paper Title: Bridging the Gap: The PrEP Cascade Paradigm Shift for Long-Acting Injectable HIV Prevention BTG Supplementary Files (6 total): S1: Clinical Trial Evidence and Safety Considerations Comprehensive review of LAI-PrEP clinical trials (HPTN 083, 084; PURPOSE-1, 2) Efficacy data across populations and geographic settings Safety profiles for cabotegravir and lenacapavir Bridge period as necessary safety framework Implications for prescription-to-injection protocols S2: Complete Intervention Library 21 evidence-based strategies for bridge period navigation Organized by intervention mechanism (eliminate, compress, navigate, remove barriers, address clinical/interpersonal, system-level redesign) Effect sizes with confidence intervals Evidence sources and implementation guidance Population-specific and barrier-specific applications Cost-effectiveness considerations S3: Global Implementation Considerations Regional variation in HIV burden and LAI-PrEP availability Healthcare system capacity and infrastructure needs Policy frameworks and regulatory requirements Integration with existing HIV prevention programs Resources for implementation in high-burden settings S4: Implementation Strategies Structural approaches to bridge period completion Clinic-level interventions and quality improvement frameworks Workforce training and capacity building Technology-enabled solutions (telemedicine, mobile delivery) Monitoring and evaluation frameworks S5: Population-Specific Implementation Guidance Adolescents (autonomy, parental consent, school coordination) Cisgender women (reproductive health, childcare, transportation) Transgender women and transgender men (affirming care, cultural competency) People who inject drugs (harm reduction integration, stigma reduction) Racial/ethnic minorities and rural populations (structural racism mitigation, geographic access) S6: Research Agenda Critical evidence gaps in LAI-PrEP implementation Prospective validation studies needed Health equity research priorities Cost-effectiveness analyses Long-term persistence and re-initiation studies Implementation science recommendations Evidence Base Parameters derived from: Clinical trials: HPTN 083 (n=4,566), HPTN 084 (n=3,224), PURPOSE-1/2 (n=10,761) Implementation studies: Real-world LAI-PrEP initiation data, CAN Community Health Network Systematic reviews: Patient navigation effectiveness, structural barrier impacts International guidelines: WHO, CDC, UNAIDS Safety surveillance studies: Islatravir clinical development, long-acting agent safety monitoring Islatravir Case Study: Safety Lessons for Long-Acting HIV Prevention Background Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor (NRTTI), represented the first long-acting oral HIV medication. Development demonstrated both promise and critical safety considerations relevant to all long-acting formulations. Clinical Development Timeline Phase 2a (IMPOWER 22): Oral PrEP trial demonstrated excellent antiviral activity and tolerability at study-defined doses Phase 2b/Treatment studies: Higher-dose capsule formulations tested; unexpected CD4 T-cell declines observed in some participants December 2021: Merck placed clinical holds on all islatravir studies (both PrEP and treatment indications) Regulatory response: FDA/EMA concurred with conservative approach despite no confirmed breakthrough infections in islatravir arms Safety Signal Details CD4 decline occurred predominantly in higher-dose formulations Signal emerged despite robust viral suppression and absence of resistance Decline was persistent in some participants even after discontinuation Mechanistic basis unclear (potential off-target effects at higher concentrations) Conservative interpretation: Long-acting = long consequences, unclear safety windows Critical Implications for LAI-PrEP Design 1. Irreversibility Principle Once a long-acting injection is administered, medication cannot be rapidly removed Any adverse events must be managed while drug concentrations remain elevated This fundamentally differs from oral medications (half-lives of hours to days) Creates regulatory imperative for extensive pre-dosing safety assessment 2. Bridge Period as Safety Framework The islatravir experience validates the bridge period as a necessary safety mechanism: Confirms HIV-negative status: Prevents dosing individuals with unrecognized acute infection Establishes baseline safety metrics: Documents CD4 count, immune function, absence of contraindications Allows medication washout planning: For future discontinuation, pre-dosing baselines essential Provides regulatory confidence: Demonstrates systematic pre-treatment evaluation Ensures informed consent: Adequate time for patient education and risk discussion 3. Long-Acting Agent Safety Monitoring Standards Islatravir experience established new standards adopted for cabotegravir and lenacapavir: Extended pre-dosing evaluation periods (18-45 days for LAI-CAB vs. 7-14 days for oral) RNA testing protocols (to detect acute infections within window period) Baseline immunological assessment mandatory Conservative dosing strategies (start with established efficacious doses, avoid dose escalation) Regular safety monitoring during maintenance dosing Rapid discontinuation protocols if safety signals emerge Safety Profile: Cabotegravir vs. Lenacapavir Cabotegravir (Long-Acting Injectable) Extensively studied (>6,000 individuals across prevention and treatment) Drug class (integrase inhibitors) has excellent established safety in treatment Primary adverse events: Injection site reactions (20-30%, mild, self-resolving) Serious adverse events directly attributable to drug: Extremely rare Key safety advantage: Decades of integrase inhibitor experience in treatment settings Bridge period role: Primarily confirms HIV-negative status; pharmacological safety well-characterized Lenacapavir (Long-Acting Injectable) Studied in 8,000+ individuals across clinical trials Novel drug class (maturation inhibitor): No prior therapeutic use Injection site reactions more common (30-40%) due to larger injection volume (600 μL) Serious adverse events: Extremely rare; no unexpected safety signals Key safety consideration: Novelty requires additional caution despite promising profile Bridge period role: Particularly critical given novel mechanism; baseline immune assessment essential Extrapolation from Islatravir: What Worked, What Didn't What Islatravir Taught Us (Safety Monitoring): ✓ Extended pre-treatment evaluation identifies safety-relevant baseline metrics ✓ Conservative regulatory approach justified for irreversible medications ✓ Regular safety monitoring protocols necessary even for drugs without signals ✓ Mechanism-of-action novelty increases precautionary principle application ✓ Off-target effects possible despite clean pharmacodynamic profile What Islatravir Revealed (Development Risks): ✗ Dose formulation changes can introduce unexpected safety concerns ✗ Small participant numbers may miss rare adverse events ✗ Long pharmacokinetic half-lives delay signal detection ✗ CD4 decline mechanisms may not be fully understood pre-approval ✗ Regulatory conservatism sometimes necessary despite absence of confirmed infections Application to Bridge Period Protocol Design The islatravir case informed current LAI-PrEP bridge period protocols: Element Islatravir Lesson LAI-PrEP Implementation Pre-dosing duration Extended evaluation needed 18-45 day bridge period standard Baseline metrics CD4, immune function critical Baseline CD4 assessment required Testing frequency Regular monitoring essential Quarterly/semi-annual safety monitoring Dose conservatism Avoid escalation Standard efficacious doses only Discontinuation planning Reversibility impossible Patient must understand permanence Population selectivity Extra caution in novel populations Extended monitoring for adolescents, pregnant individuals Mechanism novelty Adds precautionary requirement Lenacapavir (maturation inhibitor) gets extra scrutiny vs. cabotegravir (integrase inhibitor) Regulatory Framework Evolution Pre-Islatravir (2019-2021): Bridge period designed as practical testing window Focus on confirming HIV-negative status Less emphasis on irreversibility/safety framework Post-Islatravir (2021-present): Bridge period explicitly framed as safety assessment period Irreversibility principle formalized in regulatory guidance Conservative testing protocols mandatory (RNA + Ag/Ab) Regular monitoring expectations clearly defined Population-specific considerations emphasized Long-acting agents subjected to higher safety bar than oral formulations Current Best Practice (Informed by Islatravir) Pre-First Injection: Confirm HIV-negative status (RNA + Ag/Ab testing, 18-45 day window depending on exposure) Assess baseline CD4 count and immune function Screen for contraindications (active infections, hepatic/renal dysfunction) Evaluate medication interactions Ensure informed consent regarding irreversibility, long-term monitoring commitment Establish clear plan for subsequent injections and monitoring intervals During Maintenance Dosing: Regular HIV testing (quarterly minimum, more frequent if risk factors) CD4 monitoring (annually minimum for lenacapavir given novelty) Injection site assessment Medication adherence/appointment attendance monitoring Rapid communication pathway for any health concerns If Discontinuation Needed: Plan for oral PrEP transition or alternative prevention Monitor for loss of protection during transition period Continue surveillance given drug's long half-life Key Takeaway: Bridge Period as Adaptive Safety Strategy Rather than viewing the bridge period as an obstacle to overcome, the islatravir experience demonstrates its value as an adaptive safety framework that: Protects patients from potential harm via systematic baseline assessment Provides regulatory confidence in long-acting agent deployment Allows healthcare systems to demonstrate systematic preparedness Enables early identification of implementation barriers before first dose Establishes accountability and follow-up infrastructure Investment in bridge period completion is not just implementation science—it's clinical safety practice. Technical Features Configuration-driven architecture enabling parameter updates without code modification Streaming processing supporting millions of patients with <4GB RAM Mechanism diversity scoring preventing redundant intervention recommendations JSON export for reproducibility and machine learning integration Optional logit-space calculations for mathematical soundness Cross-platform compatibility (Python 3.7+, minimal dependencies) Important Notes Code and Configuration Unchanged This v3.1.0 release reflects reorganization of manuscript supplements and main text structure Core algorithm (lai_prep_decision_tool_v2_1.py) remains unchanged from v2.1.0 Configuration file (lai_prep_config.json) remains unchanged from v2.1.0 All validation results, precision metrics, and computational performance identical Changes from v2.1.0 LAI Supplements: Reorganized from 8 to 5 supplements with refined structure S1: Machine-Readable Clinical Trial Evidence (previously S1) S2: Intervention Library (previously S2, expanded with methodological details) S3: AI Readiness Assessment (new comprehensive section) S4: Code Repository (previously S4) S5: Additional Tables (consolidated from previous S5, S6, S7) BTG Supplements: Reorganized from 1 to 6 supplements with comprehensive scope S1: Clinical Trial Evidence (new, trial-specific focus) S2: Intervention Library (comprehensive implementation guide) S3: Global Implementation (new regional adaptation guidance) S4: Implementation Strategies (new clinic-level operational guidance) S5: Population-Specific Guidance (new equity-focused guidance) S6: Research Agenda (new prioritized research gaps) Clinical Validation Status Computational validation: ✓ Complete (21.2M patient scale, policy-grade precision) Prospective clinical validation: ⊗ Pending (required for implementation) Ready for: Research protocols, implementation planning, staged pilot testing Not ready for: Standalone clinical decision-making without physician oversight Intended Use Clinical implementation: Risk stratification and intervention selection at LAI-PrEP prescription Research: Prospective validation studies, algorithm refinement, implementation trials Quality improvement: Bridge period navigation program development, process optimization Policy: Resource allocation modeling, implementation planning, equity impact assessment Important Limitations Computational validation only; prospective clinical validation required Some parameters extrapolated from oral PrEP cascade (PWID, adolescents) Population categories aggregate substantial heterogeneity Real-world performance may differ from computational predictions Recommended staged implementation with systematic outcome tracking Not a substitute for clinical judgment; designed for decision support only License Software (Python code): Pharma-Restricted Open Healthcare License v1.0 Configuration/Data: CC BY 4.0 (attribution required) Documentation: CC BY 4.0 (attribution required) Supplementary Materials (LaTeX): CC BY 4.0 (attribution required) Permitted Use: Healthcare providers, researchers, academics, non-profits, and government agencies may use freely with attribution. Pharmaceutical/biotechnology companies require written permission for commercial use (patient care exception applies with notification). Publications Companion Manuscripts (Viruses Journal Special Issue: Long-Acting Antiretrovirals) Demidont, A.C. (2025). Computational Validation of a Clinical Decision Support Algorithm for Long-Acting Injectable PrEP Bridge Period Navigation at UNAIDS Global Target Scale. Viruses. (In review) Demidont, A.C. (2025). Bridging the Gap: The PrEP Cascade Paradigm Shift for Long-Acting Injectable HIV Prevention. Viruses. (In review) Citation Format: @software{demidont2025laiprep, author = {Demidont, A.C.}, title = {LAI-PrEP Bridge Period Decision Support Tool}, version = {4.1.0}, year = {2025}, publisher = {Zenodo}, doi = {10.5281/zenodo.17873201}, url = {https://zenodo.org/records/17873201} } } @article{demidont2025computational, author = {Demidont, A.C.}, title = {Computational Validation of a Clinical Decision Support Algorithm for Long-Acting Injectable {PrEP} Bridge Period Navigation at {UNAIDS} Global Target Scale}, journal = {Viruses}, year = {2025}, note = {In review} } @article{demidont2025bridging, author = {Demidont, A.C.}, title = {Bridging the Gap: The {PrEP} Cascade Paradigm Shift for Long-Acting Injectable {HIV} Prevention}, journal = {Viruses}, year = {2025}, note = {In review} } Related Identifiers Zenodo DOI: 10.5281/zenodo.17873201 GitHub Repository: https://github.com/Nyx-Dynamics/LAI-PrEP-Bridge-Tool Author ORCID: 0000-0002-9216-8569 Zenodo Metadata Summary Field Value Title LAI-PrEP Bridge Period Decision Support Tool v2.1.0: Code, Configuration, and Supplementary Materials for Viruses 2025 Manuscripts Resource Type Software Version 2.1.0 (Code & Configuration); 4.1.0 (Manuscript Supplements) Publication Date 2025-12-09 Zenodo DOI 10.5281/zenodo.17873201 License Other (Open) — Pharma-Restricted Open Healthcare License v1.0 Author Demidont, A.C. Affiliation Nyx Dynamics, LLC ORCID 0000-0002-9216-8569 Keywords HIV prevention, pre-exposure prophylaxis, long-acting injectable, cabotegravir, lenacapavir, implementation science, clinical decision support, health equity, patient navigation, bridge period, algorithm validation, computational validation, UNAIDS targets, global health Funding No specific grant from any funding agency Conflicts of Interest Author previously employed by Gilead Sciences (Jan 2020–Oct 2024), stock fully divested by Dec 2024. Research conducted independently without industry funding. Related Publications Demidont, A.C. (2025). Computational Validation of a Clinical Decision Support Algorithm for LAI-PrEP Bridge Period Navigation at UNAIDS Global Target Scale. Viruses. (In review) Demidont, A.C. (2025). Bridging the Gap: The PrEP Cascade Paradigm Shift for Long-Acting Injectable HIV Prevention. Viruses. (In review) Contact Email [e-mail] GitHub Repository https://github.com/Nyx-Dynamics/LAI-PrEP-Bridge-Tool Contact A.C. Demidont, DO Email: [e-mail] Organization: Nyx Dynamics, LLC Location: Fairfield, CT, USA Funding & Conflicts of Interest Funding: This work received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Conflicts of Interest: The author was previously employed by Gilead Sciences, Inc. (January 2020–October 2024) and held company stock that was fully divested by December 2024. This research was conducted independently without industry funding after employment concluded. The decision support tool is provided as an open-source resource. No sponsors were involved in the design, execution, interpretation, or writing of this study. Repository Contents This Zenodo archive contains: Exact code version (lai_prep_decision_tool_v2_1.py, cli.py, test_edge_cases.py) Configuration files (lai_prep_config.json, lai_prep_config_FIXED.json) Validation results and supplementary materials referenced in both manuscripts Complete reproducibility documentation All data necessary to replicate computational validation results at 21.2M patient scale Package unchanged from code/configuration perspective. Supplement reorganization reflects refined manuscript structure for clarity and emphasis on implementation guidance (BTG) vs. computational methodology (LAI). Last Updated: December 9, 2025 Version: 4.1.0 (Manuscript submission version)