Development of a Predictive Model for Sexually Transmitted Infections in Individuals Using Pre-Exposure Prophylaxis for HIV in Spain
Conditions: Sexually Transmitted Infections (STIs), HIV, PrEP
Sponsor: Hospital Universitario de Valme

Development of a Predictive Model for Sexually Transmitted Infections in Individuals 
Using Pre-Exposure Prophylaxis for HIV in Spain 
 
Principal Investigator: Anaïs Corma Gómez 
Version 3 
Date: 11/02/2025 
 
 

Background 
 
Pre-exposure prophylaxis (PrEP) is an effective and safe strategy for HIV prevention in 
men who have sex with men (MSM), transgender women, and cisgender heterosexual 
individuals (1-4). The daily combination of two antiretroviral drugs, tenofovir disoproxil 
fumarate (TDF) and emtricitabine (FTC), in a single oral tablet, has been authorized as a 
preventive treatment for HIV at both the European and national levels. It was included 
in the pharmaceutical benefits covered by the Spanish National Health System in 2019. 
Although the implementation of PrEP programs in Spain has been slower compared to 
neighboring countries and was further delayed by the SARS-CoV-2 pandemic, all 
Autonomous Communities (CCAA) currently provide this service. According to data from 
the Information System of PrEP Programs in Spain, as of September 2021, there were 
9,092 individuals on PrEP, primarily men, especially MSM. While initially targeted at 
MSM, transgender individuals, and cisgender women engaged in sex work, the eligibility 
criteria were expanded at the end of 2021 to allow any individual over 16 years old in a 
situation of vulnerability to HIV to request PrEP. The estimated number of users taking 
PrEP as of April 2023 was 18,075, according to aggregated reports from the CCAA (6). 
PrEP programs are not solely based on pharmacological measures but also incorporate 
other interventions such as condom promotion, sexual education, assisted counseling, 
substance use assessment, risk reduction, early detection and treatment of sexually 
transmitted infections (STIs), and vaccination status updates (5). All these activities are 
conducted quarterly in medical, nursing, and pharmacy consultations within Specialized 
Care Units for Infectious Diseases and Hospital Pharmacy Departments. The eligibility 
criteria include having more than 10 different sexual partners, engaging in condomless 
anal sex, using drugs associated with condomless sex (chemsex), having used post-
exposure prophylaxis (PEP) on multiple occasions, and having been diagnosed with at 
least one bacterial STI in the past year. Therefore, individuals at high risk of acquiring HIV 
infection also share a similarly high risk of other STIs. 
Despite its effectiveness in reducing HIV incidence, the high prevalence of sexually 
transmitted infections (STIs) among individuals using PrEP presents additional challenges 
in terms of public health and clinical management. While HIV infections in this context 
remain rare, STI prevalence remains significant, underscoring the need to address this 
public health concern comprehensively. In fact, STIs are the most frequently diagnosed 
clinical event during the follow-up of PrEP users. Several studies conducted in 
international cohorts have estimated a very high incidence of STIs in this population (7-
10). However, the impact of PrEP on STI incidence trends remains debated. While some 
studies suggest that initiation into the program leads to a decrease in condom use, 
thereby increasing the risk of acquiring an STI (11), others have found no such increase 
(9,10,12). Additionally, it is crucial to recognize that the PrEP-using population is 

heterogeneous, meaning that not all individuals share the same risk of acquiring an STI. 
In fact, evidence suggests that approximately 75% of STIs occur in just 25% of the PrEP 
population (12). 
 
In any case, STI screening is a fundamental pillar of the PrEP program and should be 
conducted at every clinical visit, even in asymptomatic patients, to diagnose, treat, and 
eliminate STIs, thereby interrupting the chain of transmission. However, there is 
widespread debate regarding the optimal screening frequency, as testing for certain STIs 
is costly, severe complications in men are rare, and frequent antibiotic use may 
contribute to antimicrobial resistance. On one hand, a Dutch modeling study suggested 
that testing for chlamydia and gonorrhea every three months, compared to every six 
months, would not be cost-effective according to current health economic criteria (13). 
On the other hand, two recent studies have demonstrated that biannual screenings 
could delay the diagnosis and treatment of a substantial proportion of asymptomatic 
STIs, potentially leading to increased transmission (14,15). A risk-based approach to 
determining STI screening frequency could help resolve these challenges. 
 
Since the approval and subsequent implementation of PrEP in Spain at the end of 2019, 
the demand for these services has steadily increased. In fact, access to PrEP is estimated 
to be significantly lower than the existing demand. The growing need for services, along 
with the additional burden associated with STI monitoring, is beginning to overwhelm 
the resources of PrEP-providing units. The requirement for quarterly STI screenings, 
combined with the rising number and diversity of PrEP users, poses significant logistical 
and financial challenges for healthcare systems. For these reasons, the interaction 
between this strategy and STI incidence raises fundamental questions. In our setting, 
large-scale data on STI incidence among PrEP users, its distribution across different 
population profiles, and its trends over time remain unknown. Currently, all PrEP-
providing units offer the same type of follow-up for all patients. In this context, there is 
an urgent need to develop innovative approaches to address and prevent STIs more 
efficiently within the PrEP population. Artificial intelligence (AI) can provide robust tools 
for the development of predictive models that integrate a wide range of risk factors, 
individual characteristics, and their dynamic changes. This would enable more accurate 
risk stratification and the personalization of preventive and follow-up interventions. A 
personalized approach, in which each individual is stratified according to their risk of 
experiencing the studied events, could aid in clinical decision-making. Moreover, this 
approach would not only facilitate the early identification of individuals at higher risk but 
also allow for the effective design of a tailored care and follow-up model for these 
patients. This would optimize resources, reduce the burden on both individuals and the 
healthcare system, and enhance efficiency while maximizing health outcomes. 

Optimizing follow-up not only improves efficiency and reduces costs but also enhances 
the quality of care by focusing on personalization and active prevention. Ultimately, this 
project aims to make a substantial contribution to public health by improving the 
management of STIs in a specific and dynamic population. 
 
 

References 
1. Grant RM et al. NEJM.2010; 363:2587-99.  
2. Grant RM et al. Lancet Infectious Diseases. 2014; 14: 820-9.  
3. Baeten JM et al. NEJM. 2012; 369: 399-410.  
4. Drak D et al. AIDS. 2021; 35: 2319-26.  
5. GeSIDA. Recomendaciones sobre la Profilaxis Pre-Exposición para la Prevención de la 
Infección por VIH en España. Marzo 2023. Disponible en [http://.gesida-
seimc.org/category/guias-clinicas/otras-guias-vigentes/].  
6. División de Control de VIH, ITS, Hepatitis virales y Tuberculosis. Sistema de información 
de programas de Profilaxis Pre-exposición al VIH en España (SIPrEP). Informe de 
resultados noviembre 2019-mayo 2023. Ministerio de Sanidad, julio 2023. Disponible en 
[https://siprep.isciii.es/documentos].  
7. Hoornenborg E et al. Lancet HIV. 2019; 6: e447-55.  
8. Traeger MW et al. JAMA. 2019; 321 (14): 1380-90.  
9. Traeger MW et al. Lancet Infectious Diseases. 2022; 22:1231-41.  
10. 
Ayerdi 
O 
et 
al. 
EIMC. 
2024 
[Epub 
ahead 
of 
print] 
DOI 
number:10.1016/j.eimc.2024.01.003.  
11. Traeger MW et al. CID. 2018; 67: 676-86.  
12. McManus H et al. JAMA Network Open. 2020; 3 (12):e2030806.  
13. Van Wifferen et al. Sex Transm Infect. 2021; 97: 607-12.  
14. Tang EC et al. AIDS. 2020; 34: 1181-6.  
15. Jongen VW et al. Sex Transm Infect. 2023; 99: 149-155. 
 
 

Hypothesis 
It is possible to accurately define the risk of acquiring a sexually transmitted infection 
(STI) in individuals using PrEP who are included in the follow-up program. 
Objectives 
➢ Primary Objective: 
• 
Develop and validate a predictive model for STI acquisition in individuals using 
PrEP within the national provision program for this strategy. 
➢ Secondary Objectives: 
• 
Estimate the incidence of STIs in the cohort, both globally and by type of 
infection. 
• 
Assess the evolution of STI diagnoses within the program and model their long-
term trend, both globally and by specific pathogen. 
• 
Evaluate the proportion of asymptomatic STIs diagnosed within the screening 
program. 
• 
Study behavioral changes in the socio-sexual domain of individuals initiating PrEP. 
• 
Identify potential candidates for the “Doxy-PEP” strategy (doxycycline use as 
post-exposure prophylaxis for chlamydia and syphilis). 
 
 
 

Methods 
 
• Design and Patients: This is a multicenter, ambispective cohort study involving 24 
Spanish hospitals. All individuals using PrEP and enrolled in the follow-up program 
will be included (see PrEP criteria). 
• Follow-up: The entry point into the program will be considered the baseline visit. 
From that point onward, patients will be followed quarterly according to national 
PrEP follow-up protocols in Spain. At each visit, the following assessments will be 
conducted: 
-Risk evaluation 
-Clinical and laboratory assessment 
-Sample collection for STI diagnosis, including: serum, pharyngeal swab, urethral 
exudate or urine sample, rectal swab 
If patients present specific STI-related symptoms, targeted sample collection will be 
performed for diagnostic purposes. The presence of symptoms suggestive of an STI will 
be defined as the development of any of the following: mucocutaneous ulcerative or 
other lesions, dysuria, urethral discharge, proctalgia, pathological stool products, rectal 
tenesmus. 
• Variables 
➢ Outcome Variables: 
 Primary Outcome: Development of an STI (Yes/No). The following STIs will be 
considered: Syphilis, Neisseria gonorrhoeae (NG) infection, Chlamydia trachomatis (CT) 
infection, Lymphogranuloma venereum (LGV), Mycoplasma genitalium (MG) infection, 
Genital herpes, Hepatitis A, Hepatitis B, Hepatitis C, HIV infection, Mpox 
 Secondary Outcome: Number of STIs diagnosed 
 
➢ Explanatory Variables: 
    Sociodemographic variables: Age, gender identity, sex, sexual orientation. 
    Variables related to sexual practices: 
        Receptive and/or insertive sex 
        Frequency of condom use 
        Number of sexual partners 

        Engagement in chemsex and route of drug use 
        Sex work and frequency of visiting sex exchange venues 
 
    Variables related to STIs: 
        Clinical presentation 
        Site of infection 
        Vaccination status for hepatitis A (HAV), hepatitis B (HBV), human papillomavirus 
(HPV), and smallpox 
 
    Variables related to PrEP use: 
        Previous use of PrEP and/or post-exposure prophylaxis (PEP) 
        PrEP regimen (continuous/on-demand) 
        Adherence to PrEP 
 
• Data Collection 
Clinical, epidemiological, analytical, and microbiological data will be recorded in a Case 
Report Form (CRF) specifically designed for this study. For data collection and 
management, the RedCap® platform has been selected due to its security, flexibility, and 
ability to structure databases in a standardized manner, facilitating both data monitoring 
and traceability. Data entry will be performed locally by professionals external to the 
research team, who provide this service to study participants. A semi-annual remote 
monitoring of all data recorded in the CRF will be conducted, along with on-site 
monitoring in specific cases, as determined by the data monitoring team. 
• Laboratory Determinations 
These determinations will be performed as part of routine clinical practice in the 
Microbiology Unit Laboratory of each participating center. Diagnosis of Chlamydia 
trachomatis (CT) and Neisseria gonorrhoeae (NG) will be conducted using nucleic acid 
detection techniques in the following sample types: 
        -Urine 
        -Endocervical swab 
        -Urethral swab 

        -Rectal swab 
        -Pharyngeal swab 
Screening for HIV, syphilis, and viral hepatitis will be performed using serological 
techniques. Syphilis reinfection will be defined as a four-fold or greater increase in RPR 
titers. For individuals with positive anti-HCV antibodies, HCV RNA PCR testing will be 
performed to rule out active reinfection. 
 
Statistical Analysis 
Once recruitment is completed, the study population will be stratified into three subsets, 
ensuring that the distribution of patients with respect to the outcome variable remains 
similar across all groups. Two-thirds of the population will be used for developing 
predictive models, while the remaining third will serve as the validation group for model 
assessment. 
• 
Incidence Calculation: 
o The quarterly incidence will be calculated by dividing the number of STI 
cases by the total number of individuals during that period. 
o Incidence rates will be expressed per 100 person-years of follow-up, with 
exact 95% confidence intervals (CIs). 
o Participants will contribute to person-time calculations until their last STI 
screening or until administrative censoring of follow-up, whichever 
occurs first. 
o Individuals who do not receive a PrEP prescription within three months 
after their previous prescription will be considered to have discontinued 
PrEP, and their follow-up will be censored three months after their last 
prescription. 
o If a participant resumes PrEP at a later stage, they will be re-entered into 
the analysis, with their person-time calculation restarting from their 
subsequent STI screening. 
• 
Descriptive Analysis: 
o Categorical variables will be expressed as absolute and relative 
frequencies. 
o Continuous variables will be reported as medians (Q1–Q3). 
o Comparison of proportions: Chi-square test or Fisher’s exact test. 

o Comparison of continuous variables: Student’s t-test or Mann-Whitney U 
test. 
• 
Multivariate Analysis: 
o To identify factors associated with STI acquisition, both bivariate and 
multivariate logistic regression analyses will be performed. 
o Variables showing an association with p < 0.050 in the bivariate analysis 
will be included in the multivariate model. 
o The significance level will be set at p < 0.05, and results will be expressed 
as odds ratios (ORs) with 95% confidence intervals. 
• 
Machine Learning Models for Predictive Analysis: 
o Various machine learning models will be trained to predict future STI 
infections in new patients. 
o While interpretable models (e.g., decision trees, rule-based models) will 
be prioritized, more complex models (e.g., ensemble methods and neural 
networks) will also be explored if they demonstrate significantly superior 
performance (Bonaccorso, G. et al., 2018). 
o Hyperparameter tuning will be performed using cross-validation on the 
training set. 
o The best-performing models will then be evaluated on the validation set 
to assess their ability to generalize to new patients not included in the 
training phase. 
• 
Model Evaluation and Comparison: 
o Different performance metrics will be used, accounting for class 
imbalance and the differential costs associated with prediction errors 
(Raeder, T. et al., 2012). 
o Model comparison will follow a Bayesian approach, as suggested by 
Benavoli et al. (2017), or alternative statistical comparisons (Garcia, S. et 
al., 2008). 
o A Region of Practical Equivalence (ROPE) will be defined through a 
consensus between theoretical considerations and clinical expertise. 
o Among the best models falling within the ROPE, the most interpretable 
model will be selected. 
• 
Software: 

o Statistical and model-fitting analyses will be performed using: 
▪ 
SPSS version 26.0 (IBM Corporation, Somers, NY, USA) 
▪ 
STATA 16.0 (StataCorp LP, College Station, TX, USA) 
▪ 
Python (statsmodels, scikit-learn, and other relevant libraries) 
(latest stab 
 
• Ethical Considerations 
This research study will be conducted in accordance with the ethical principles outlined 
in the Declaration of Helsinki by the World Medical Association (WMA), as well as the 
following legal and regulatory frameworks: Law 14/2007 on Biomedical Research; Law 
41/2002, the fundamental law regulating patient autonomy, rights, and obligations 
regarding clinical information and documentation; Organic Law 3/2018 on Personal Data 
Protection and Digital Rights;  Good Clinical Practice (GCP) guidelines; Regulatory 
authority requirements for the verification of original documents and study 
audits/inspections. All collected data will undergo an encryption process to ensure 
patient anonymity.  Additionally, approval for this study has been approved by the 
Research Ethics Committee (REC) of the Southern Health Management Area of Seville 
(coordinating center) and the respective ethics committees of all participating centers.