DOI: 10.5281/zenodo.17797511
title: LAI-PrEP Bridge Period Decision Support Tool v4.1.0: Code, Configuration, and Supplementary Materials

description: 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
acdemidont@nyxdynamics.org


GitHub Repository
https://github.com/Nyx-Dynamics/LAI-PrEP-Bridge-Tool




Contact

A.C. Demidont, DO



Email: acdemidont@nyxdynamics.org

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)
description: Version ChangeLog

# LAI-PrEP Bridge Period Decision Support Tool ## Version History --- ## v4.1.0 (December 2025) **Release Type:** Manuscript Supplement Reorganization **Code Status:** UNCHANGED (v2.1.0) **Configuration Status:** UNCHANGED (v2.1.0) **Data Status:** UNCHANGED **Zenodo DOI:** 10.5281/zenodo.17873201 ### What Changed Reorganization of supplementary materials for two companion manuscripts submitted to *Viruses* journal special issue on Long-Acting Antiretrovirals. No changes to core algorithm, validation results, or computational performance. ### LAI Manuscript Supplements **From:** 8 supplements → **To:** 5 supplements | Previous | New | Content | |----------|-----|---------| | S1 | S1 | Machine-Readable Clinical Trial Evidence | | S2 | S2 | Intervention Library (expanded with methodology) | | S3, S6 | S3 | AI Readiness Assessment (consolidated & expanded) | | S4 | S4 | Code Repository & Technical Documentation | | S5, S7, S8 | S5 | Additional Statistical Tables (consolidated) | **Rationale:** Consolidated algorithm safety/ethics (S3), statistical rigor (S5), and code accessibility (S4) into streamlined structure emphasizing computational methodology validation. ### BTG Manuscript Supplements **From:** 1 supplement → **To:** 6 supplements | New | Content | |-----|---------| | S1 | Clinical Trial Evidence & Safety Considerations | | S2 | Complete Intervention Library | | S3 | Global Implementation Considerations | | S4 | Implementation Strategies (clinic-level) | | S5 | Population-Specific Implementation Guidance | | S6 | Research Agenda | **Rationale:** Expanded from single intervention inventory to comprehensive implementation guidance spanning clinical evidence, global policy, operational strategy, health equity, and future research priorities. ### Files Affected **Code:** None **Configuration:** None **Validation Data:** None **New/Modified Files:** - LAI_S1.tex → LAI_S1.tex (structure unchanged, title refined) - LAI_S2.tex (expanded with complete methodology section) - LAI_S3.tex (new: consolidated AI readiness material) - LAI_S4.tex (unchanged) - LAI_S5.tex (consolidated: additional tables) - BTG_S1.tex through BTG_S6.tex (new: comprehensive 6-supplement structure) ### Computational Validation Results **Unchanged from v2.1.0:** - Precision: ±0.018 percentage points at 21.2M scale - Unit tests: 100% pass rate (18/18 edge cases) - Convergence: Stable across 1K to 21.2M patients - Population alignment: All predictions within trial ranges - Predicted impact: 81.6% relative improvement (23.96% → 43.50%) ### Why This Release Was Necessary Zenodo versioning policy requires new DOI assignment when manuscript supplements are reorganized (not merely updated). The new v3.1.0 release ensures: - Transparency of supplement structure at time of submission - Persistent archive matching published manuscript citations - Clear distinction between "computation/methodology" (LAI) vs. "implementation/equity" (BTG) focus - Complete reproducibility documentation for both companion papers ### Backward Compatibility ✓ **Fully compatible** — All code, configuration, and computational results identical to v2.1.0 ✓ **No revalidation needed** — Validation metrics, precision, and scaling results unchanged ✓ **Configuration portable** — lai_prep_config.json identical; works with both versions ### Citation Information **If citing the tool itself:** ``` @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} } ``` **If citing the LAI computational manuscript:** ``` @article{demidont2025computational, author = {Demidont, A.C.}, title = {Computational Validation of a Clinical Decision Support Algorithm for {LAI-PrEP} Bridge Period Navigation at {UNAIDS} Global Target Scale}, journal = {Viruses}, year = {2025} } ``` **If citing the BTG implementation manuscript:** ``` @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} } ``` --- ## v2.1.0 (November 2025) **Initial manuscript submission version** - Core algorithm and configuration finalized - Comprehensive validation at 21.2M scale - Initial supplementary materials for Viruses submission - 100% unit test pass rate --- ## Version Comparison Table | Aspect | v2.1.0 | v4.1.0 | |--------|--------|--------| | Code (lai_prep_decision_tool_v2_1.py) | ✓ | ✓ (identical) | | Configuration (lai_prep_config.json) | ✓ | ✓ (identical) | | Validation precision | ±0.018 pp | ±0.018 pp | | Test suite pass rate | 100% | 100% | | Clinical trial coverage | HPTN 083/084, PURPOSE 1/2 | (unchanged) | | LAI supplements | 8 | 5 (reorganized) | | BTG supplements | 1 | 6 (expanded) | | Computational result changes | — | None | | New DOI required | — | Yes (supplement changes) | --- --- ## Safety Focus: Islatravir Case Study & Long-Acting Agent Safety Monitoring ### Why This Matters for v4.1.0 The manuscript supplements (particularly LAI S1) include comprehensive analysis of islatravir clinical development and its implications for current LAI-PrEP safety frameworks. This represents a fundamental reframing: **the bridge period is not an implementation obstacle but a necessary safety safeguard.** ### Islatravir Timeline (2021 Clinical Hold) | Date | Event | Implication | |------|-------|------------| | 2019-2021 | Phase 2a/2b trials | Excellent antiviral activity, tolerability at approved doses | | Oct 2021 | Higher-dose trials initiated | Unexpected CD4 T-cell declines in some participants | | Dec 2021 | Clinical hold issued | Merck halts all islatravir studies (PrEP + treatment) | | 2022-2025 | Regulatory impact | FDA/EMA establish stricter safety standards for all long-acting agents | ### Key Safety Lessons Incorporated into LAI-PrEP Protocols **1. Irreversibility Principle** - Long-acting medications cannot be rapidly removed if safety concerns arise - This fundamentally changes risk calculus vs. oral medications - Creates imperative for systematic pre-treatment baseline assessment **2. Novel Drug Classes Require Extended Evaluation** - Cabotegravir (integrase inhibitor): Decades of treatment experience = moderate precaution - Lenacapavir (maturation inhibitor): Novel mechanism = higher precaution, extended bridge period - Off-target effects possible despite clean primary mechanism **3. Bridge Period as Safety Framework** Current LAI-PrEP bridge protocols (18-45 days) explicitly address islatravir lessons: - Confirm HIV-negative status with RNA testing (catches acute infections) - Establish baseline CD4 count and immune function - Screen for contraindications and drug interactions - Ensure informed consent regarding irreversibility - Provide time for education and relationship-building with healthcare team **4. Regulatory Evolution (Post-Islatravir)** - Long-acting agents held to higher safety bar than oral PrEP - Regular monitoring expectations formalized - Population-specific considerations (adolescents, pregnant individuals, immunocompromised) - Discontinuation planning required pre-treatment ### Reframing the Bridge Period **Old Model (Pre-Islatravir):** - Bridge period = technical delay waiting for test results - Viewed as barrier to LAI-PrEP uptake - Minimal infrastructure invested **New Model (Post-Islatravir):** - Bridge period = intentional safety assessment period - Viewed as evidence of clinical rigor and patient protection - Infrastructure and patient support critical - Missed bridge periods represent clinical safety failures, not just implementation gaps ### Implementation Corollary The shift from "eliminating the bridge period" to "ensuring bridge period completion" reflects this safety reframing. Key interventions in the tool address: - **Transportation support** → enables appointment attendance - **Patient navigation** → builds relationship, ensures follow-up - **Telemedicine** → increases access while maintaining safety monitoring - **Mobile delivery** → brings services to patients without eliminating pre-injection assessment - **Accelerated testing** → compresses bridge duration while maintaining safety (RNA testing reduces window period from 33-45 days to 10-14 days) **None of these interventions eliminate the bridge period**—they optimize its completion and patient experience while maintaining safety standards. --- ## Zenodo Metadata Summary (v4.1.0) | 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** | Pharma-Restricted Open Healthcare License v1.0 | | **Author** | Demidont, A.C. | | **Affiliation** | Nyx Dynamics, LLC | | **ORCID** | 0000-0002-9216-8569 | | **Resource Status** | Published | | **Visibility** | Public (record and files publicly accessible) | | **GitHub Repository** | https://github.com/Nyx-Dynamics/LAI-PrEP-Bridge-Tool | | **Contact Email** | acdemidont@nyxdynamics.org | --- *Last Updated: December 9, 2025* *Version: 4.1.0 (Manuscript submission version)*