Adriana Cervo

Background: Lenacapavir (LEN) is a first-in-class, long-acting HIV-1 capsid inhibitor, approved for the treatment of heavily treatment-experienced (HTE) people with HIV (PWH) with multidrug resistance (MDR). To date, few data are available on resistance profiles in real life. Methods: Paired plasma and PBMC samples from nine HTE PWH with MDR enrolled in the PRESTIGIO Registry receiving LEN in combination with an optimized background regimen were collected before (baseline) and during LEN treatment. Next-generation sequencing was performed using in-house protocols. LEN susceptibility was assessed by single-cycle assay. Intra-patient viral evolution was evaluated through quasispecies distance analysis. Results: At baseline, no major LEN resistance-associated mutations were detected; the accessory capsid polymorphism T107A was identified as a minority variant (5.9%) in one case, with phenotypic assays confirming full LEN susceptibility (mean fold-change: 1.2). Participants received LEN for a median [IQR] of 19.8 [18.5–23.2] months. Two individuals started LEN with undetectable viremia and maintained suppression. The other seven participants were viremic; six achieved viral suppression, with one experiencing a blip. One low-adherent participant exhibited persistent viremia with Q67K and K70H as the majority variants in both plasma (98.5%; 97.8%) and PBMCs (75.7%; 75.6%), conferring a 2081-fold reduction in LEN susceptibility. Intra-host variability in the capsid and pol regions remained low over time and across compartments. Conclusions: In this case series of HTE PWH with MDR, LEN was highly associated with maintenance or achievement of virological suppression and limited virus evolution, with only one participant remaining viremic and showing a majority highly LEN-resistant variant.

We compared the effectiveness of tenofovir (TFV)‐based triple regimens (TT) to TFV‐sparing dual therapies (DT) in virologically suppressed, HBsAg−/HBcAb+ people living with HIV (PLWH). We emulated a target trial including adults PLWH from five University Hospitals, with HBsAg−/HBcAb+ serostatus, starting a TT with unsuppressed serum HIV‐RNA and reaching HIV‐RNA < 50 cp/mL (baseline). PLWH starting a DT (3TC + bPI or DTG, DTG + RPV, DOR + DTG or long‐acting CAB + RPV) were considered in the “treatment”‐group only if they switched within a 1‐year grace period; all other PLWH were considered “control”‐group. To emulate randomization, participants were cloned at baseline and assigned the opposite strategy, then censored at the time of strategy‐deviation and assigned a weight based on the inverse‐probability of being uncensored. Probabilities of 5‐year virological failure (VF; two consecutive HIV‐RNA > 50 cp/mL or a single HIV‐RNA ≥ 200 cp/mL) were estimated through a weighted Kaplan–Meier estimator. Overall, 415 PLWH were eligible for study analysis: 71 (17.1%) started a DT (3TC‐based: 78.9%) during follow‐up. They were mainly men (329, 79.3%), with a median age of 48 years. In the weighted analysis, the estimated probabilities of VF were: 29.3% for DT and 29.9% for TT at 5 years (difference: 0.5%; 95% CI: −28.7, +21.6). A higher VF risk was seen in the subset of PLWH with undetectable HBsAb at the longest follow‐up available (4 years), independently of treatment group: 15.5% and 36.8% with DT and TT, respectively (difference: −21.3%; 95% CI: −30.3, −13.8). Switch to a TFV‐sparing DT, compared with continuing a TT, was not associated with an increased risk of VF in PLWH and prior HBV infection.

Objectives: To assess whether an electronic Clinical Decision Support System (eCDSS), embedded within a hospital-wide antimicrobial stewardship (AMS) programme, can meaningfully reduce antimicrobial use and improve prescribing quality in routine clinical practice. Methods: We conducted a prospective quasi-experimental interrupted time-series study in a 1200-bed tertiary-care hospital in Italy (April 2022–April 2024). The eCDSS, integrated into computerized order entry and linked to pharmacy data, triggered real-time identification of high-impact antimicrobial prescriptions and enabled infectious diseases (IDs)-led prospective audit and feedback. Primary outcomes were overall antibiotic use and carbapenem consumption; secondary outcomes included guideline adherence, stewardship intensity, antimicrobial duration and costs. Results: Across 5890 prescriptions in 2604 patients (9336 ID evaluations), the intervention was associated with a significant and sustained reduction in overall antibiotic consumption (CL: −3.27 DDD/100 patient-days, 95% CI −6.06 to −0.47; CT: −0.25 DDD/100 patient-days/month, 95% CI −0.44 to −0.07). Carbapenem use showed a parallel significant decline across both DDD and DOT metrics. In contrast, no significant reductions were observed for other monitored antibiotics or antifungals. Prescribing quality improved over time, with increasing adherence to local guidelines (CT: +1.59%/month; P = 0.001). Despite high-intensity stewardship activity (mean 1.6 ID interventions per prescription), antimicrobial expenditures remained stable, although a downward trend was observed. Conclusions: An eCDSS integrated into a human-led AMS programme was associated with a significant reduction in overall antibiotic and carbapenem use and improved prescribing quality. These findings demonstrate that digital stewardship tools do not replace but amplify ID expertise and pharmacy collaboration, enabling sustained optimization of antimicrobial use.

Background: The risk of developing low-level viral rebound (LLVR) after achieving HIV-RNA suppression with two-drug regimens (2DR) compared to triple regimens (3DR) remains uncertain. Methods: We conducted a matched 1:3 case-control study nested within the ICONA cohort including persons with HIV (PWH) who achieved virological suppression (≥2 consecutive HIV-RNA≤50copies/ml over 6 months) after November 11, 2014 (baseline, BL). Cases were defined as PWH experiencing a single HIV-RNA of 51-199 copies/ml after BL (index date); controls as those who maintained HIV-RNA ≤50 copies/mL up to the index date and matched for history of care gaps and number of drugs failed. The cumulative incidence of LLVR after virological suppression was estimated using Kaplan-Meier methods and conditional logistic regression models evaluated the association between the currently ART regimen [2DR (dolutegravir/lamivudine, dolutegravir/rilpivirine, dolutegravir/doravirine or cabotegravir/riplivirine) vs. 3DR (doloutegravir, bictegravir, rilpivirine, doravirine, darunavir/b, atazanavir/b-based with a backbone of tenofovir and lamivudine or emtricitabine)] and LLVR risk. Sensitivity analyses restricted cases to those with two consecutive LLVR event. Results: Among 1,033 PWH [261 cases, 772 matched controls; 21% female, median age 43 years (Interquartile range, IQR, 34-51), BL CD4 count 601/mm3 (IQR 379-826)], 2DR use was 25% in cases versus 29% in controls (p=0.23). Two years after viral suppression, cumulative LLVR incidence was 2.7% (95% CI 2.3-3.1) when considering all single LLVR events and 1.8% (1.4-2.1) when limited to two consecutive values. After adjusting for confounding, evidence was inconclusive [aOR 0.86, 95% CI 0.57-1.29].)]. Conclusion: Despite the wide range of plausibility, we can exclude a risk of LLVR higher than 29% when using 2DR vs. 3DR regimens.

Dolutegravir plus lamivudine (DTG+3TC) is widely used as a two-drug switch regimen for virologically suppressed PWH. We report long-term real-world data on effectiveness, tolerability, immunological recovery and metabolic/cardiovascular outcomes in a large, multicentre Italian cohort. We performed a retrospective observational analysis of participants in the ODOACRE cohort who switched to DTG+3TC between January 2015 and January 2025 across eight Italian centres. Inclusion criteria were age ≥18, HIV-RNA 500 000 copies/mL (aHR 2.205) predicted VF, whereas longer prior virological suppression was protective (per year aHR 0.869). During 9721.6 PYFU we observed 362 TDs (3.72 per 100 PYFU), with probabilities of regimen maintenance of 94.4%, 83.5% and 78.7% at weeks 48, 240 and 480, respectively. In our real-world cohort with extended follow-up, DTG+3TC as a switch regimen was associated with durable virological suppression and favourable tolerability. Metabolic findings should be considered descriptive and exploratory, within the limits of an observational, uncontrolled study.

Introduction: This study aims to assess the impact of proactive Infectious Disease Specialist (IDS) interventions, in addition to standard antimicrobial stewardship (AMS) practices, triggered by real-time microbiological alerts, on improving the appropriateness and timeliness of antimicrobial prescriptions in hospitalized patients with bloodstream infections (BSIs). Methods: We conducted a prospective, single-center, pre-post interventional study at the University Hospital of Modena, Italy. Adult inpatients with monomicrobial BSIs between June 2022 and March 2023 were included. During the intervention phase (November 2022–March 2023), real-time microbiological alerts were automatically delivered to IDS consultants, who proactively reviewed therapy. Primary outcomes included the time to effective therapy (TTE) and the time to appropriate therapy (TTA). Secondary outcomes encompassed the duration of antimicrobial therapy, 14 and 30-day mortality from BSI, and hospital length of stay. Results: A total of 446 BSI episodes were analyzed (211 pre-intervention, 235 post-intervention). Post-intervention, the rate of appropriate therapy significantly increased (97.4% versus 76.2%, P < 0.001), and TTE was significantly shorter (0.63 versus 0.87 days, P = 0.022). No statistically significant reduction in TTA was observed (1.97 versus 2.37 days, P = 0.081). Early IDS intervention (<48 h) was associated with the shortest TTE and TTA. No significant differences were observed in mortality or hospital stay. Kaplan–Meier analysis showed a higher probability of receiving effective and appropriate therapy earlier in the post-intervention phase (log-rank test P = 0.014; 0.072, respectively). Subgroup analysis showed TTE improvements across MDR pathogens. Conclusions: A proactive intervention of IDS, based on automatic microbiological alert, in addition to routine AMS activities, is significantly associated with improved prescription appropriateness, reducing TTE.

Background: Phase 3 studies have shown long-acting (LA) cabotegravir/rilpivirine to be effective and tolerable as maintenance therapy in people with HIV (PWH). However, real-life data on their effectiveness are limited. Methods: All PWH enrolled in the Icona Cohort who started LA cabotegravir/rilpivirine with HIV-RNA < 50 copies/mL were included. Times to treatment discontinuation (TD) and to virological failure (VF50, two consecutive HIV-RNA >50 copies/mL or one >1000 copies/mL followed by ART switch) were estimated by the Kaplan–Meier method. Cox regression models, adjusted for age, sex and mode of HIV transmission and stratified by the centre, were employed. Results: Overall, 583 PWH started LA cabotegravir/rilpivirine. Six VF50 were observed, with a 1 year estimated cumulative probability of virological failure of 1.2% (95% CI, 0.5%–3.0%). Resistance-associated mutations for rilpivirine and cabotegravir were detected in 3/4 and 4/4 participants with VF50, respectively, for which the genotypic resistance test was performed. The 1 year cumulative probability of TD was 11.4% (95% CI, 8.6%–14.9%), mainly caused by toxicity/adverse events (73.2%). Multivariable analysis identified heterosexual intercourse and IV drug use as significant risk factors for TD compared with MSM. Conclusions: This analysis demonstrated the short-term effectiveness of cabotegravir/rilpivirine in a real-life setting showing minimal incidence of virological failure but a notable probability of discontinuation due to toxicity or adverse events.

Background: Our aim was to compare epidemiological, clinical and treatment characteristics, and outcomes between patients with diagnoses of coronavirus disease 2019–associated pulmonary aspergillosis (CAPA) or putative invasive pulmonary aspergillosis (PIPA), without hematological cancers. Methods: Retrospective, monocentric comparative observational cohort study, including nonhematological patients treated for invasive pulmonary aspergillosis between 2018 and 2022. Primary study end points were risk factors for 30-day mortality and clinical failure. To account for the imbalance in antifungal treatment allocation, a propensity score weighting approach was adopted. Results: A total of 209 patients were included, 93 (44.5%) with CAPA and 116 (55.5%) with PIPA; 144 (68.9%) we admitted to the intensive care unit. Patients with PIPA had higher Charlson Comorbidity Index values (mean [SD], 5.8 [2.6]; range, 0–14) and higher prevalences of chronic obstructive pulmonary disease (30.7%), solid cancer (36.8%), liver cirrhosis (12.3%), and concomitant immunosuppressive therapies (26.1%). Patients with CAPA received more invasive mechanical ventilation (70.5%) and corticosteroids (90.1%), more frequently had positive galactomannan (GM) results with bronchoalveolar lavage (80.5%), and had longer mean hospital stays (62.7 [SD, 52.1; range, 8–276] days) and intensive care unit stays (36 [30.7; 2–168] days). No differences in clinical cure or mortality rates were observed between groups. In multivariable analysis, isavuconazole was the only independent factor for clinical cure, reported also in the propensity score matching analysis (odds ratio, 0.41 [95% confidence interval, .16–1.03]; P = .06). A positive serum GM result was independently associated with 30-day mortality (hazard ratio, 1.78 [95% confidence interval, 1.02–3.10]; P = .04). Conclusions: Patients with CAPA have fewer comorbid conditions and higher fungal burden than those with PIPA, but clinical outcomes are similar between groups. Isavuconazole was an independent predictor for clinical cure, and serum GM positivity an independent predictor for 30-day mortality.

Background: Data regarding the effectiveness of vancomycin-resistant Enterococci (VRE)–active prophylaxis for preventing early post–liver transplantation (LT) VRE infections in VRE-colonized patients are scarce. Methods: 131 pre-LT VRE-colonized patients who underwent LT were enrolled in a retrospective, observational, multicenter study. The incidence of early-onset VRE infections was compared between patients who received active prophylaxis for VRE and those who did not. Results: Sixty-nine (52.7%) and 62 (47.3%) patients were enrolled in the VRE-active and non–VRE-active prophylaxis group. Tigecycline was the most common drug prescribed as VRE-active for prophylaxis (55/69; 79.7%). There was no significant difference in the number of patients who developed early-onset VRE infections in the VRE-active versus non–VRE-active groups at 7 (0 [0.0%] vs 2 [3.2%]; P = .222), 14 (4 [5.7%] vs 4 [6.4%]; P = 1.000), and 30 (6 [8.7%] vs 8 [12.9%]; P = .621) days post-LT, respectively. Risk of early-onset VRE infection within 30 days was not lower in the VRE-active group (log-rank P = .16 with Kaplan-Meier analysis; odds ratio [OR]: .643; 95% CI: .210–1.969; P = .439 with univariate analysis). Conversely, early infections caused by any pathogen were significantly lower in the VRE-active prophylaxis group compared with the control group (11 [15.9%] vs 20 [32.2%]; P = .047). Tigecycline prophylaxis was associated with a lower risk of early-onset infections with multivariate analysis (OR: .106; 95% CI: .015–.745; P = .024) and after adjusting for propensity score (adjusted OR: .146; 95% CI: .031–.708; P = .017). Conclusions: VRE-active prophylaxis at LT did not reduce the incidence of early post-LT VRE infections and should not be recommended.