Anna Maria Cattelan’s research while affiliated with University of Padua and other places

Background and Importance Despite the end of the global health emergency, a vulnerable portion of the population remains at high-risk of developing severe forms of COVID-19. To address this, two antiviral drugs are used for early treatment: remdesivir (RDV), administered via intravenous infusion for 3-day outpatient, and nirmatrelvir/ritonavir (NRM/RTV), administered orally over 5 days. Aim and Objectives This study aims to conduct a cost analysis between RDV and NRM/RTV in the early treatment of severe COVID-19. Material and Methods A network meta-analysis was performed, based on the latest systematic review comparing RDV and NRM/RTV,¹ to estimate the relative risk (RR) of hospitalisation and severe adverse events. Assuming 100,000 eligible patients, two cost scenarios were estimated: all patients treated with RDV versus all treated with NRM/RTV. Costs include the ex-factory price of the drugs, hospitalisation, management of adverse events and outpatient settings for RDV, estimated using a ‘bottom-up’ micro-costing approach. Event incidence data from the approval RCT for RDV were used. Results The network meta-analysis reveals only indirect comparisons between RDV and NRM/RTV. The RR of hospitalisation for NRM/RTV compared to RDV is 2,80 (95% CI: 0,33–24,07), while for severe adverse events it is 0,92 (95% CI: 0,31–2,74). The SUCRA rank for hospitalisation is 0,91 for RDV and 0,58 for NRM/RTV; for adverse events it is 0,72 for RDV and 0,78 for NRM/RTV. The ex-factory cost is €1.800,00 for RDV and €1.336,29 for NRM/RTV. Hospitalisation costs €8.081,29, adverse event management costs €3.725,00, and the outpatient setting for RDV costs €137,58. The total estimated cost in the RDV scenario is €218.891.438,10 and in the NRM/RTV scenario €180.267.256,68. Conclusion and Relevance The analysis indicates no significant difference between therapies in preventing hospitalisations, but the SUCRA rank shows a higher efficacy and lower safety of RDV compared to NRM/RTV. In the RDV scenario, the total cost would be €197.758.000,00 for treatment, €14.465.688,10 for hospitalisations, and €6.667.750,00 for adverse events. In the NRM/RTV scenario, the total cost would be €133.629.000,00 for treatment, €40.503.926,68 for hospitalisations, and €6.134.330,00 for adverse events, resulting in savings of €38.624.181,42. References and/or Acknowledgements • Zur, et al. - Efficacy and safety of antiviral treatments for symptomatic COVID-19 outpatients: Systematic review and network meta-analysis 2024. Conflict of Interest No conflict of interest

Background and Importance HIV Pre-Exposure Prophylaxis (PrEP) is an established preventive therapy, made reimbursable in Italy since August 2023.¹ In this context, the prescription form was digitised with the goal of improving its clinical management and monitoring therapeutic adherence. This tool assists clinicians by streamlining the prescription process and enabling quick therapies’ monitoring for individuals at risk of HIV. However, understanding gaps between prescribed therapy and patient adherence is crucial for improving outcomes. Aim and Objectives This analysis aimed to evaluate patient adherence to PrEP, assess how well patients followed the prescribed regimen and to identify factors related to suboptimal adherence. Material and Methods Data extracted from digital form and pharmaceutical flows were crossed to create a dataset of individuals with at least one PrEP refill between July 2023 and September 2024. Only patients receiving Continuous Dosing Therapy (CDT) were included in the analysis, and those who chose On-Demand therapeutic regimen (ODT), interrupted or switched it, were excluded. Adherence was assessed by calculating the proportion of days covered (PDC),² with a threshold of ≥80% considered adherent. PDC data were compared with self-reported adherence from patients during therapeutic planning. Results A total of 515 individuals were collected, consisting of 509 males (98.8%), three females, and three with unspecified gender, with a median age of 38 years (IQR 32–46). Of these, 213 (41.4%) opted for CDT regimen, while 302 (58.6%) chose ODT regimen. The final analysed sample comprised 179 users (34.7%) who maintained the CDT, with 100% self-reported adherence. However, our analysis revealed that 21 users had a PDC ≤80%, indicating suboptimal adherence, 131 users had a PDC ≥80%, reflecting adequate adherence. Additionally, 27 users had a PDC ≥120%, suggesting potential overuse, which warrants further investigation. Conclusion and Relevance The digital prescription tool proves to be an effective system for monitoring and evaluating adherence. Despite high self-reported adherence, discrepancies between reported and actual adherence were observed, underscoring the need for continuous and objective monitoring. These findings highlight the importance of collaboration between infectious disease specialists and pharmacists to enhance clinical support. Future efforts should prioritise identifying and addressing adherence barriers while strengthening patient support to ensure sustained efficacy in HIV prevention References and/or Acknowledgements • https://www.aifa.gov.it/en/-/aifa-approva-rimborsabilita-farmaci-per-la-prep • McCormick et al. 2024. doi:10.1002/pds.5729 Conflict of Interest No conflict of interest

Background Major adverse cardiovascular events (MACEs) may contribute to the high morbidity in people with four-class drug-resistant HIV (4DR-PWH). Objectives To explore the probability of MACEs in 4DR-PWH compared with non-4DR controls. Methods This was a retrospective, propensity score-matched cohort study on 4DR-PWH (cases) and non-4DR-PWH (controls), on ART, without previous MACEs. Controls were matched with cases in a 4:1 ratio for age, sex-assigned-at-birth and ART duration. Incidence rates (IRs) and incidence rate ratio (IRR) of MACEs with 95% CIs were modelled by Poisson regression. Cumulative probabilities of the first incident MACE were estimated by Kaplan–Meier curves. A multivariable stepwise Cox proportional hazards model estimated predictors of incident MACEs among covariates with univariable P < 0.100. Results Overall, 223 4DR-PWH and 797 non-4DR-PWH were evaluated. During a median (IQR) follow-up of 8.2 (5.4–11.1) years [1833 person-years of follow-up (PY)], 23/223 (10.3%) 4DR-PWH developed 29 MACEs, IR = 1.6 (95% CI = 1.1–2.3)/100 PY. During a median follow-up of 8.4 (5.2–11.0) years (6450 PY), 42/797 (5.3%) non-4DR controls had 45 MACEs, IR = 0.7 (95% CI = 0.5–0.9)/100 PY, IRR (4DR/non-4DR) = 2.3 (95% CI = 1.4–3.6). The cumulative probabilities of the first MACE were more than doubled in 4DR-PWH (P = 0.006). At multivariable analysis, an increased risk of MACEs was associated with 4DR status [adjusted hazard ratio (aHR) = 1.9; 95% CI = 1.0–3.4], after adjusting for age, sex-assigned-at-birth, HIV load, CD4+ nadir, total cholesterol, HDL cholesterol, diabetes mellitus, statin use and baseline HCV serostatus. Conclusions In PWH, MDR is significantly associated with a higher risk of cardiovascular events. Prompt implementation of prevention strategies is mandatory in this fragile population.

Objective Integrating electronic health record (EHR) data with other resources is essential in rare disease research due to low disease prevalence. Such integration is dependent on the alignment of ontologies used for data annotation. The international classification of diseases (ICD) is used to annotate clinical diagnoses, while the human phenotype ontology (HPO) is used to annotate phenotypes. Although these ontologies overlap in the biomedical entities they describe, the extent to which they are interoperable is unknown. We investigate how well aligned these ontologies are and whether such alignments facilitate EHR data integration. Materials and Methods We conducted an empirical analysis of the coverage of mappings between ICD and HPO. We interpret this mapping coverage as a proxy for how easily clinical data can be integrated with research ontologies such as HPO. We quantify how exhaustively ICD codes are mapped to HPO by analyzing mappings in the unified medical language system (UMLS) Metathesaurus. We analyze the proportion of ICD codes mapped to HPO within a real-world EHR dataset. Results and Discussion Our analysis revealed that only 2.2% of ICD codes have direct mappings to HPO in UMLS. Within our EHR dataset, less than 50% of ICD codes have mappings to HPO terms. ICD codes that are used frequently in EHR data tend to have mappings to HPO; ICD codes that represent rarer medical conditions are seldom mapped. Conclusion We find that interoperability between ICD and HPO via UMLS is limited. While other mapping sources could be incorporated, there are no established conventions for what resources should be used to complement UMLS.

Candidemia and invasive candidiasis (IC) are causes of morbidity and mortality in healthcare settings, with notable differences between children and adults. Understanding the species distribution and antimicrobial susceptibility profiles of clinical isolates can guide empiric therapy in patients at risk of IC. This study investigated the incidence and antifungal susceptibility patterns of yeasts involved in IC in pediatric and adult patients from 2019 to 2023. The average incidence of IC was 0.715 per 1000 patients, increasing over the study period; infants had the highest incidence rates. Over half of the IC episodes occurred in intensive care units (ICUs). Non-albicans Candida (NAC) species represented the most frequently isolated species in adults and children (55.96% and 50.0%, respectively), with the prevalence of C. parapsilosis (26.45% and 14.7%, respectively), N. glabratus (14.97% and 8.82%, respectively) and C. tropicalis (4.36% and 2.94%, respectively). C. lusitaniae was identified in 14.7% of pediatric IC cases. In NAC species, antifungal resistance has also increased over the five years of the study: 69.12% were resistant to azoles and 7.35% were resistant to micafungin. Resistance was higher in pediatric patients. Our study highlights differences in IC characteristics between pediatric and adult populations and emphasizes the importance of targeted antifungal stewardship in ICU patients with NAC invasive infections.

Background The potential efficacy of early combination therapy, based on an antiviral plus a monoclonal antibody, for COVID-19 in severely immunocompromised patients is matter of debate. Objectives Our aim was to describe the impact on clinical outcomes of COVID-19 treatments in severely immunocompromised individuals, evaluating differences between a combination and a monotherapy. Methods We included severely immunocompromised outpatients with mild-to-moderate COVID-19 who received an early treatment (either monotherapy with nirmatrelvir/ritonavir or remdesivir or the combination of an antiviral plus sotrovimab). We then assessed differences between the two treatment strategies on three main outcomes (30-day mortality, access to emergency department, hospitalization), separately and as a composite by using a propensity score weighted (PSW) approach. Results Eighty one severely immunocompromised patients were included, 39 receiving early combination therapy and 42 receiving monotherapy. No significant difference was observed in the 30-day mortality rate and hospitalization rate between subjects in the two groups, while access to the emergency department following treatment administration was significantly higher in people who received a combination therapy. After applying the PSW, it was observed that combination therapy impacted favourably on the composite outcome, in a statistically significant fashion. In addition, PSW approach for mortality showed that age was the only significant factor influencing the death as stand-alone outcome. Conclusions Early combination therapy showed a favourable impact on a composite outcome (including mortality, hospitalizations and access to emergency department) in severely immunocompromised hosts who were all vaccinated. However, further studies are needed to support our results.

Background Implementation level of long-acting injectable agents cabotegravir/rilpivirine (LAI CAB/RPV) for human immunodeficiency virus (HIV) treatment in Italy is still not known. The aim of this study is to identify the status of implementation of LAI CAB-RPV and its barriers. Materials and methods A cross-sectional online survey was conducted among infectious diseases (ID) physicians and nurses belonging to the ICONA network in Italy. Three validate 4-items measures were used: Acceptability of Intervention Measure (AIM), Intervention Appropriateness Measure (IAM) and Feasibility of Intervention Measure (FIM). Results Out of 61 ICONA centres, 38 (62%) completed the survey: 57.9% were academic centres, 42.1% were hospital-based. In total, 104 respondents were ID physicians (57.4%), 77 were nurses (42.5%); 4.5% of all PWH followed at the 38 centres started LAI CAB/RPV at time of study. Centres taking care of >1000 PWH reported 95% application of procedures for LA implementation, higher than other centres (P = 0.009). Mean score of AIM was (16.0, standard deviation, SD, 3.3), of IAM (16.0, SD 3.0) and FIM (16.0, SD 2.9). A linear correlation was found between AIM and the number of people with HIV who started LAI CAB/RPV (25–50 versus <25, coefficient of correlation [b] 2.57, 95%CI 0.91–4.60, P = 0.004), academic versus hospital-based centres (b −1.59, 95%CI −2.76–0.110044, P = 0.007) and the absence of preliminary systematic assessment of staff (b −1.98, 95%CI −3.31–0.65, P = 0.004). Implementation barriers were not significantly different according to the number of PWH/centre. Conclusions LAI CAB/RPV implementation was low, with a great variability according to centre size. Tailored and centre-specific interventions to address barriers and to optimize the LA treatment implementation should be designed.

Background To clarify whether next-generation sequencing (NGS) can be useful for resistance assessment in virologically suppressed highly treatment-experienced (HTE) individuals with MDR HIV. Methods Ninety-one participants from the PRESTIGIO Registry were included. NGS was performed on HIV-DNA at 1%, 5% and 20% cut-offs; major drug resistance mutations (DRMs) were evaluated and compared with those detected in historical plasma genotypic resistance testing (h-GRT). APOBEC editing was also characterized. Results Participants had a complex and long treatment history [median 23 (IQR 21–25) years of ART exposure) and had been virologically suppressed since a median of 3 (IQR 2–5) years. Among all major DRMs detected by HIV-DNA NGS and/or h-GRT, 30% were exclusively found through NGS. The highest detection rate of historical major DRMs was reached with NGS set at 1%, but unusual substitutions and extensive APOBEC hypermutations suggest technical issues and poor clinical relevance in the 1%–5% interval. At NGS set at 5%, 67.2% of historical major DRMs were detected. The number of major DRMs detected exclusively by DNA-NGS as minority variants (frequency 5%–20%) was significantly higher in individuals who later experienced virological rebound compared with those who maintained virological control [median 2 (IQR 1–3) versus 1 (0–2), P = 0.030] and positively correlated with viraemia levels at rebound (rho = 0.474, P = 0.030). Conclusions In non-viraemic people with an MDR virus, HIV-1 DNA NGS set at 5% is an acceptable technical cut-off that might help to reveal mutations with a potential clinical relevance. Moreover, the number of minority resistance mutations additionally detected by NGS might be associated with loss of virological control.

Objectives To evaluate polypharmacy, anticholinergic burden (ACB) and drug–drug interactions (DDIs) in people with four-class-resistant HIV (4DR-PWH). Methods We performed a cross-sectional study, including 4DR-PWH from the PRESTIGIO Registry taking at least one non-antiretroviral drug. Polypharmacy was defined as taking five or more non-antiretroviral drugs. ACB was calculated using the ACB scale: 0 = no AC effect, 1–2 = low/moderate risk, ≥3 = high AC risk. Participants’ characteristics by ACB score were compared using the Kruskal–Wallis test, and Spearman's correlation coefficient was used to assess linear relationships. DDIs were evaluated using the Liverpool database. Results Overall, 172 4DR-PLWH were evaluated: 75.6% males, median age 49.9 years (IQR = 45.6–56), 62 (27.1%) on polypharmacy, 124 (72.1%) using a boosting agent and 72 (41.8%) with four or more antiretrovirals. Based on ACB, 128 (74.45%), 33 (19.2%) and 11 (6.4%) had a no, low/moderate and high AC risk, respectively. The most common AC drugs were β-blockers (12.2%), diuretics (8.7%) and antidepressants (8.7%). The high ACB was significantly related to the number of drugs/person (r = 0.33, P < 0.0001) and the number of clinical events (r = 0.222, P = 0.004). Overall, 258 DDIs were found between antiretrovirals and co-medications in 115 (66.8%) PWH, and 14 (8.1%) PWH received contraindicated drug combinations. Conclusions In 4DR-PWH, polypharmacy, DDIs and the proportion of people with moderate/high AC burden were high. In 4DR-PWH undetectability achievement and maintenance is the priority and use of boosted PIs is common. A strict collaboration (infectious diseases specialists, virologists, pharmacologists) is needed to limit the risk of ACB and DDIs and to explore the advantages of new antiretrovirals.