Influence of efavirenz and 8-hydroxy-efavirenz plasma levels on cognition and central nervous system side effects.

OBJECTIVES: To investigate whether efavirenz (EFV) or 8-hydroxy-EFV (8-OH-EFV) plasma levels are associated with neurocognitive impairment and central nervous system (CNS) side effects. METHODS: We conducted a cross-sectional analysis to explore the potential links between EFV/8-OH-EFV levels and cognitive performance or CNS-related side effects in patients screened within a randomized trial involving a switch from EFV to rilpivirine. The Mann-Whitney test was employed to compare drug levels in patients with or without cognitive impairment, depression, anxiety, sleep disorder or CNS symptoms. Additionally, Spearman's test was used to assess correlations between drug levels and test scores. RESULTS: Among 104 patients, neither EFV nor 8-OH-EFV levels were linked to cognitive impairment, although trends towards higher EFV levels were observed in those with impaired executive function (p = 0.055) and language performances (p = 0.021). On the other hand, elevated 8-OH-EFV levels, but not EFV levels, were associated with more CNS side effects (222 vs. 151 ng/mL, p = 0.027), depressive symptoms (247 vs. 164 ng/mL, p = 0.067) and sleep impairment (247 vs. 164 ng/mL, p = 0.078). Consistently, a trend towards a correlation between EFV levels and lower z-scores in executive function and motor function was observed, while 8-OH-EFV levels, but not EFV levels, were directly correlated with symptom scores. CONCLUSIONS: Higher levels of 8-OH-EFV were associated with CNS side effects, while EFV levels were only marginally associated with cognitive performance, thus suggesting that EFV and its metabolite may act differently in determining detrimental neurological effects.

Anti-spike antibody level is associated with the risk of clinical progression among subjects hospitalized with COVID-19 pneumonia: results from a retrospective cohort study.

PURPOSE: Antibodies against SARS-CoV-2 spike (anti-S) may confer protection against symptomatic COVID-19. Whether their level predicts progression among those with COVID-19 pneumonia remains unclear. METHODS: We conducted a retrospective cohort study to assess predictors of anti-S levels and whether anti-S titer is associated with death or mechanical ventilation (MV). Adults hospitalized for COVID-19 pneumonia between July 2021 and July 2022 were enrolled if anti-S had been measured within 72 h of admission. Predictors of anti-S level were explored using multivariable quantile regression. The association between anti-S levels and 30-day death/MV was investigated via multivariable logistic regression. Analyses were stratified by vaccine status. RESULTS: The median anti-S level was 1370 BAU/ml in 328 vaccinated and 15.5 BAU/ml in 206 unvaccinated individuals. Among the vaccinated, shorter symptom duration (p = 0.001), hematological malignancies (p = 0.002), and immunosuppressive therapy (p = 0.004) were associated with lower anti-S levels. In the unvaccinated group, symptom duration was the only predictor of anti-S levels (p < 0.001). After 30 days, 134 patients experienced death or MV. Among vaccinated individuals, higher anti-S levels correlated significantly with lower death/MV risk (per log2 increase, OR 0.88, 95%CI 0.81-0.97), irrespective of age and solid malignancies. Among unvaccinated, a marginally protective effect was observed (OR 0.86, 95%CI 0.73-1.01), independent of age, immunosuppressive therapy, and diabetes. Adjustment for monoclonal antibody treatment strengthened the association (OR 0.81, 95%CI 0.68-0.96). CONCLUSION: This study suggests that levels of anti-S antibodies can predict critical or fatal outcomes in COVID-19 pneumonia patients, regardless of vaccination. Whether anti-S Ab could guide risk assessment and vaccination boosting merits further evaluation.

Mpox Virus in the Pharynx of Men Having Sex with Men: A Case Series.

The recent Mpox virus (MPV) outbreak in Europe and North America, primarily among men who have sex with men (MSM), raised concerns about various transmission sources. We examined patients with Mpox from an urban STI center in Lombardy, Italy, between May and August 2022. Demographic, transmission, and clinical data were collected using a standardized form. Initial and subsequent tests were conducted using the RealStar Orthopoxvirus PCR Kit 1.0 (Altona Diagnostics, Hamburg, Germany) for skin lesions and oropharyngeal swabs. A total of 15 patients were recruited, all MSM, with 40% being HIV-positive. Almost all reported recent unprotected sexual activity. Oropharyngeal symptoms were observed in a minority, and oral cavity lesions were present in 20% of cases. MPV DNA was detected in skin lesions of 93% of patients and in oropharyngeal swabs of 87%. Skin samples exhibited a higher viral load than pharyngeal samples, with the latter persisting longer. Prospective follow-up of 11 individuals revealed an average pharyngeal persistence of 5.3 days beyond skin lesion clearance, reaching up to 80 days in an immunosuppressed case. Our findings indicate that MPV replication can persist in the pharynx asymptomatically and for an extended period.

Impact of interactive computerised decision support for hospital antibiotic use (COMPASS): an open-label, cluster-randomised trial in three Swiss hospitals.

BACKGROUND: Computerised decision-support systems (CDSSs) for antibiotic stewardship could help to assist physicians in the appropriate prescribing of antibiotics. However, high-quality evidence for their effect on the quantity and quality of antibiotic use remains scarce. The aim of our study was to assess whether a computerised decision support for antimicrobial stewardship combined with feedback on prescribing indicators can reduce antimicrobial prescriptions for adults admitted to hospital. METHODS: The Computerised Antibiotic Stewardship Study (COMPASS) was a multicentre, cluster-randomised, parallel-group, open-label superiority trial that aimed to assess whether a multimodal computerised antibiotic-stewardship intervention is effective in reducing antibiotic use for adults admitted to hospital. After pairwise matching, 24 wards in three Swiss tertiary-care and secondary-care hospitals were randomised (1:1) to the CDSS intervention or to standard antibiotic stewardship measures using an online random sequence generator. The multimodal intervention consisted of a CDSS providing support for choice, duration, and re-evaluation of antimicrobial therapy, and feedback on antimicrobial prescribing quality. The primary outcome was overall systemic antibiotic use measured in days of therapy per admission, using adjusted-hurdle negative-binomial mixed-effects models. The analysis was done by intention to treat and per protocol. The study was registered with ClinicalTrials.gov (identifier NCT03120975). FINDINGS: 24 clusters (16 at Geneva University Hospitals and eight at Ticino Regional Hospitals) were eligible and randomly assigned to control or intervention between Oct 1, 2018, and Dec 31, 2019. Overall, 4578 (40·2%) of 11 384 admissions received antibiotic therapy in the intervention group and 4142 (42·8%) of 9673 in the control group. The unadjusted overall mean days of therapy per admission was slightly lower in the intervention group than in the control group (3·2 days of therapy per admission, SD 6·2, vs 3·5 days of therapy per admission, SD 6·8; p<0·0001), and was similar among patients receiving antibiotics (7·9 days of therapy per admission, SD 7·6, vs 8·1 days of therapy per admission, SD 8·4; p=0·50). After adjusting for confounders, there was no statistically significant difference between groups for the odds of an admission receiving antibiotics (odds ratio [OR] for intervention vs control 1·12, 95% CI 0·94-1·33). For admissions with antibiotic exposure, days of therapy per admission were also similar (incidence rate ratio 0·98, 95% CI 0·90-1·07). Overall, the CDSS was used at least once in 3466 (75·7%) of 4578 admissions with any antibiotic prescription, but from the first day of antibiotic treatment for only 1602 (58·9%) of 2721 admissions in Geneva. For those for whom the CDSS was not used from the first day, mean time to use of CDSS was 8·9 days. Based on the manual review of 1195 randomly selected charts, transition from intravenous to oral therapy was significantly more frequent in the intervention group after adjusting for confounders (154 [76·6%] of 201 vs 187 [87%] of 215, +10·4%; OR 1·9, 95% CI 1·1-3·3). Consultations by infectious disease specialists were less frequent in the intervention group (388 [13·4%] of 2889) versus the control group (405 [16·9%] of 2390; OR 0·84, 95% CI 0·59-1·25). INTERPRETATION: An integrated multimodal computerised antibiotic stewardship intervention did not significantly reduce overall antibiotic use, the primary outcome of the study. Contributing factors were probably insufficient uptake, a setting with relatively low antibiotic use at baseline, and delays between ward admission and first CDSS use. FUNDING: Swiss National Science Foundation. TRANSLATIONS: For the French and Italian translations of the abstract see Supplementary Materials section.

In search of lost time: A timing evaluation of antimicrobial prescribing with and without a computerized decision support system using clinical vignettes.

BACKGROUND: We implemented a computerized decision support system (CDSS) integrated in the in-house computerized physician order entry (CPOE) system to assist physicians with antimicrobial prescribing decisions in the context of the multicenter cluster-randomized COMPASS trial (NCT03120975). Some physicians in the intervention wards complained about the perceived extra-time associated with the use of the CDSS compared with routine prescribing through CPOE. The aim of this study was to compare the time needed to prescribe antimicrobials with and without the CDSS. METHODS: Physicians with and without previous experience with the COMPASS CDSS working at our hospital in Geneva, Switzerland, were recruited to prescribe antimicrobials using clinical vignettes. Physicians without experience received a brief explanation of the CDSS. Each physician received 2 groups of 5-7 clinical vignettes randomly selected from a pool of 28. Each group of vignettes included prescriptions with different levels of complexity (empiric versus targeted or pre-defined treatment, dose adjustment for renal function, oral switch, treatments for which COMPASS does not provide recommendations or where a deviation was necessary). Prescriptions were completed using the standard CPOE (first set), then using COMPASS (second set). A print version of the local antimicrobial guidelines was available for consultation. Time to complete each prescription was recorded (including time needed to consult paper guidelines). The Mann-Whitney test was used for comparisons. Consultation of guidelines booklet and concordance with local guidelines were assessed. RESULTS: Twenty-five physicians were recruited. Thirteen (52%) had previously used COMPASS. Among them, 11 (85%) estimated the extra-time being above 1 min. We evaluated a total of 296 vignettes. Overall, the median time to complete a prescription was 55.5 s (IQR 38-86) using COMPASS and 50 s (IQR 31-88) using the standard CPOE (p = 0.24). Concordance of prescriptions with local guidelines was similar with the 2 systems (127/148, 85.8% for both), but consultation of paper guidelines was more frequent when prescribing without the CDSS (49.3% (73/148) vs 22.3% (33/148)). CONCLUSIONS: The increased time required for prescribing using COMPASS is overestimated by end-users. Information collected in the study will be used to streamline the prescribing process via COMPASS and increase acceptance.

Factors determining the adherence to antimicrobial guidelines and the adoption of computerised decision support systems by physicians: A qualitative study in three European hospitals.

BACKGROUND AND OBJECTIVES: Antimicrobial stewardship (AMS) programs aim to optimize antibiotic use and reduce inappropriate prescriptions through a panel of interventions. The implementation of clinical guidelines is a core strategy of AMS programs. Nevertheless, their dissemination and application remain low. Computerised decision support systems (CDSSs) offer new opportunities for semi-automated dissemination of guidelines. This qualitative study aimed at gaining an in-depth understanding of the determinants of adherence to antimicrobial prescribing guidelines and CDSSs adoption and is part of a larger project, the COMPASS trial, which aims to assess a CDSS for antimicrobial prescription. The final objective of this qualitative study is to 1) provide insights from end-users to assist in the design of the COMPASS CDSS, and to 2) help with the interpretation of the quantitative findings of the randomised controlled trial assessing the COMPASS CDSS, once data will be analysed. METHODS: We conducted semi-structured individual interviews among in-hospital physicians in two hospitals in Switzerland and one hospital in France. Physicians were recruited by convenience sampling and snowballing until data saturation was achieved. RESULTS: Twenty-nine physicians were interviewed. We identified three themes related to the potential barriers to guideline adherence: 1) insufficient clarity, accessibility and applicability of guidelines, 2) need of critical thinking skills to adhere to guidelines and 3) impact of the team prescribing process and peers on physicians in training. As to the perception of CDSSs, we identified four themes that could affect their adoption: 1) CDSSs are perceived as time-consuming, 2) CDSSs could reduce physicians' critical thinking and professional autonomy and raise new medico-legal issues, 3) effective CDSSs would require specific features, such as ease of use and speed, which affect usability and 4) CDSSs could improve physicians' adherence to guidelines and patient care. DISCUSSION: CDSSs have the potential to overcome several barriers for adherence to guidelines by improving accessibility and providing individualised recommendations backed by patient data. When designing CDSSs, mixed clinical and information technology teams should focus on user-friendliness, ergonomics, workflow integration and transparency of the decision-making process.

Overlooked cases of HIV infection: An Italian tale of missed diagnostic opportunities.

BACKGROUND: Late diagnoses are still a cause of increased HIV-related morbidity and mortality despite the availability of highly effective treatments. The aim of this study was to identify indicator conditions (ICs) in late presenters with HIV infection (LPs) that may represent missed opportunities of undertaking earlier HIV testing. METHODS: The medical records of LPs referred to a specialist clinic in Milan, Italy, between 2011 and 2017 were reviewed to assess the frequency of ICs during the five years preceding diagnosis. Logistic regression analysis was used to investigate the factors associated with missed opportunities of making an earlier diagnosis. RESULTS: The analysis considered 203 LPs (60.6% of the patients newly diagnosed as having HIV infection during the study period). Most had had ≥1 medical encounter in the five years before diagnosis, and 54 (26.6%) had been diagnosed as having ≥1 IC without undergoing HIV testing. The most frequent ICs were herpes zoster (19.8%), constitutional symptoms (17.4%) and lympho/thrombocytopenia (12.8%), and the missed opportunities for testing occurred in the settings of primary care (44.9%), specialist medical (38.2%) or surgical services (11.3%), and emergency departments (5.6%). Twenty-five (53.2%) of the 47 subjects with a non AIDS-defining IC had AIDS at the time of the diagnosis of HIV infection. Subjects aged >60 years were at increased risk of missed diagnostic opportunities (aOR 4.80, p = 0.008). CONCLUSION: Implementing IC-guided HIV testing in non-specialist settings is an essential means of reducing late diagnoses of HIV infection even in the case of older subjects.

How to Develop and Implement a Computerized Decision Support System Integrated for Antimicrobial Stewardship? Experiences From Two Swiss Hospital Systems.

Background: Computerized decision support systems (CDSS) provide new opportunities for automating antimicrobial stewardship (AMS) interventions and integrating them in routine healthcare. CDSS are recommended as part of AMS programs by international guidelines but few have been implemented so far. In the context of the publicly funded COMPuterized Antibiotic Stewardship Study (COMPASS), we developed and implemented two CDSSs for antimicrobial prescriptions integrated into the in-house electronic health records of two public hospitals in Switzerland. Developing and implementing such systems was a unique opportunity for learning during which we faced several challenges. In this narrative review we describe key lessons learned. Recommendations: (1) During the initial planning and development stage, start by drafting the CDSS as an algorithm and use a standardized format to communicate clearly the desired functionalities of the tool to all stakeholders. (2) Set up a multidisciplinary team bringing together Information Technologies (IT) specialists with development expertise, clinicians familiar with "real-life" processes in the wards and if possible, involve collaborators having knowledge in both areas. (3) When designing the CDSS, make the underlying decision-making process transparent for physicians and start simple and make sure to find the right balance between force and persuasion to ensure adoption by end-users. (4) Correctly assess the clinical and economic impact of your tool, therefore try to use standardized terminologies and limit the use of free text for analysis purpose. (5) At the implementation stage, plan usability testing early, develop an appropriate training plan suitable to end users' skills and time-constraints and think ahead of additional challenges related to the study design that may occur (such as a cluster randomized trial). Stay also tuned to react quickly during the intervention phase. (6) Finally, during the assessment stage plan ahead maintenance, adaptation and related financial challenges and stay connected with institutional partners to leverage potential synergies with other informatics projects.

Durability of INI-containing regimens after switching from PI-containing regimens: a single-centre cohort of drug-experienced HIV-infected subjects.

PURPOSE: Integrase inhibitor (INI)-containing regimens are increasingly replacing protease inhibitor(PI)-containing regimens in clinical practice. The aim of this study was to evaluate the determinants of the durability of INI-containing regimens after the switch. PATIENTS AND METHODS: We retrospectively analysed all of the people with HIV infection attending the University of Milan's Infectious Diseases Unit at Luigi Sacco Hospital who were switched from a PI- to an INI-containing regimen between April 2008 and March 2017. The probability of remaining on an INI-containing regimen was estimated using Kaplan-Meier curves, and the baseline clinical predictors of INI-containing regimen durability were assessed using a multivariable Cox proportional hazard regression model. RESULTS: Three hundred and twelve patients were included in the analysis. The median time of observation was 21 months (interquartile range 10-36 months). The main reasons for switching from a PI-containing regimen to an INI-containing regimen were toxicities (31.4%) and simplification (31.1%). Univariate analysis revealed no difference in the probability of INI discontinuation between the patients treated with raltegravir, dolutegravir or elvitegravir (p=0.060), but the multivariable Cox regression model showed that the patients treated with dolutegravir were at less risk of discontinuation than those treated with raltegravir (adjusted hazard ratio 0.49, 95% confidence interval 0.26-0.95; p=0.034). CONCLUSION: Switching from a PI- to an INI-containing regimen may be an option for patients under virological control. The patients switched to dolutegravir were less likely to discontinue the INI than those switched to raltegravir. Our findings support this therapeutic strategy and highlight the durability and efficacy of dolutegravir containing-regimens after switching from a PI-containing regimen.

Burden of Exposure to Potential Interactions Between Antiretroviral and Non-Antiretroviral Medications in a Population of HIV-Positive Patients Aged 50 Years or Older.

BACKGROUND: As HIV-infected patients aged 50 years or older are at increased risk of comorbidities and multidrug treatments, we examined their exposure to the potential drug-drug interactions (PDDIs) of antiretroviral (ARV) and other medications. METHODS: This cross-sectional study involved the patients aged 50 years or older receiving ARV and non-ARV medications at our clinic. PDDIs were identified using the University of Liverpool HIV Drug Interaction Checker. Logistic regression models were used to assess risk factors for PDDIs. The American Geriatrics Society Beers Criteria were used to identify potentially inappropriate medications (PIMs). RESULTS: A total of 395 (53.9%) of 744 patients showed ≥1 PDDI: 47.4% ≥ 1 amber-PDDI (comedications requiring appropriate management) and 5.6% ≥ 1 red-PDDI (contraindicated comedications). A higher risk of PDDIs was associated with the use of ≥5 medications (P < 0.001), of antiosteoporotics (P < 0.001), calcium channel blockers (P < 0.001), anti-benign prostatic hypertrophy agents (P < 0.001), hypnotics/sedatives (P = 0.022), and anticoagulants (P = 0.006). A higher risk of red-PDDIs was associated with the use of antacids (P < 0.001), anti-benign prostatic hypertrophy agents (P < 0.001) and antipsychotics (P = 0.023). The use of nucleoside reverse transcriptase inhibitor + nonnucleoside reverse transcriptase inhibitor and nucleoside reverse transcriptase inhibitor + integrase strand transfer inhibitor rather than protease inhibitor-based regimens was associated with a reduced risk of PDDIs (P < 0.001). Overall, 119 (16.0%) patients were receiving PIMs (mainly hypnotics/sedatives) and 49 (41.2%) of them had PDDIs able to increase the blood levels of these medications. CONCLUSIONS: Older patients with HIV are highly exposed to PDDIs between ARVs and comedications. The knowledge of their complete medication regimens and the screening for PDDIs and PIMs is therefore crucial to prevent drug-related adverse outcomes in this population.