Long-acting drugs: people's expectations and physicians' preparedness. Are we readying to manage it? An Italian survey.

To evaluate patients' expectations regarding long-acting antiretroviral agents and preferences about where to receive them. Multicenter cross-sectional survey-based study. Through an online survey, we asked people living with human immunodeficiency virus to judge their relationship with daily antiretroviral therapy (ART) and to give their opinion about long-acting drugs. We also collected data regarding the age of the patients, their site of follow-up, time since the diagnosis, and compliance to ART. Two hundred forty-two patients aged 18 to 79 years were included in the study: 58 (24%) females, 182 (75.2%) males, and 2 (0.8%) male-to-female transgenders. 81.8% of the said population had a good relationship with ART. 33.6% of them consider daily ART an obligation and a restriction to their freedom. One hundred forty-three (59.1%) patients already knew about long-acting drugs before our interview, and 215 (88.8%) patients were interested in it. One hundred fifty-six (64.4%) interviewees said they would still be interested in hospital-available injective long-acting drugs, although 57.9% of the patients would rather receive them at home. The data emerging from our survey reveal that around 90% of the people living with HIV are interested in changing their actual treatment with a long-acting one. Moreover, for the first time to our knowledge, such a high number of patients showed an enthusiastic response to the new opportunity to be treated directly at home. The introduction of these new drugs could be revolutionary and represents an important step toward treatment simplification.

The challenge of infectious diseases consultations in the emergency department: an Italian nationwide survey.

Diagnosis and management of infectious diseases (ID) at the emergency department (ED) are challenging due to the peculiar setting and the available diagnostic tools. The involvement of an ID consultant has been described to improve clinical outcomes and antimicrobial stewardship (AMS) programs. An online survey was sent to 100 Italian Departments of Infectious Diseases affiliated with the Italian Society of Infectious Diseases and Tropical Medicine (SIMIT). The primary objective of our study was to describe the characteristics of ID services in Italian EDs to identify possible challenges and shortcomings and provide tips to improve the management of patients. Secondary objectives included the evaluation of diagnostic capability and the management of patients with suspected or confirmed ID. Seventy-six out of the 100 SIMIT centers, 32 (42.1%) of which were teaching hospitals, answered the survey. In 62 (82.7%) centers, consultations were performed by the IDs specialist on call. In 29 (38.2%) centers, there was a formal AMS program, and 32 (42.7%) had protocols for antibiotic use in the ED. Microbiological tests to be performed before starting antibiotic treatment in the ED were clearly defined in 44 (57.9%) hospitals. This survey highlighted several challenges in the current organization of ID consultations in Italian EDs.

Enoxaparin for thromboprophylaxis in hospitalized COVID-19 patients: The X-COVID-19 Randomized Trial.

BACKGROUND: It is uncertain whether higher doses of anticoagulants than recommended for thromboprophylaxis are necessary in COVID-19 patients hospitalized in general wards METHODS: This is a multicentre, open-label, randomized trial performed in 9 Italian centres, comparing 40 mg b.i.d. versus 40 mg o.d. enoxaparin in COVID-19 patients, between April 30 2020 and April 25 2021. Primary efficacy outcome was in-hospital incidence of venous thromboembolism (VTE): asymptomatic or symptomatic proximal deep vein thrombosis (DVT) diagnosed by serial compression ultrasonography (CUS), and/or symptomatic pulmonary embolism (PE) diagnosed by computed tomography angiography (CTA). Secondary endpoints included each individual component of the primary efficacy outcome and a composite of death, VTE, mechanical ventilation, stroke, myocardial infarction, admission to ICU. Safety outcomes included major bleeding. RESULTS: The study was interrupted prematurely due to slow recruitment. We included 183 (96%) of the 189 enrolled patients in the primary analysis (91 in b.i.d., 92 in o.d.). Primary efficacy outcome occurred in 6 patients (6.5%, 0 DVT, 6 PE) in the o.d. group and 0 in the b.id. group (ARR 6.5, 95% CI: 1.5-11.6). The absence of concomitant DVT and imaging characteristics suggests that most pulmonary artery occlusions were actually caused by local thrombi rather than PE. Statistically nonsignificant differences in secondary and safety endpoints were observed, with two major bleeding events in each arm. CONCLUSIONS: No DVT developed in COVID-19 patients hospitalized in general wards, independently of enoxaparin dosing used for thromboprophylaxis. Pulmonary artery occlusions developed only in the o.d. group. Our trial is underpowered and with few events.

The incremental value of computed tomography of COVID-19 pneumonia in predicting ICU admission.

Triage is crucial for patient's management and estimation of the required intensive care unit (ICU) beds is fundamental for health systems during the COVID-19 pandemic. We assessed whether chest computed tomography (CT) of COVID-19 pneumonia has an incremental role in predicting patient's admission to ICU. We performed volumetric and texture analysis of the areas of the affected lung in CT of 115 outpatients with COVID-19 infection presenting to the emergency room with dyspnea and unresponsive hypoxyemia. Admission blood laboratory including lymphocyte count, serum lactate dehydrogenase, D-dimer and C-reactive protein and the ratio between the arterial partial pressure of oxygen and inspired oxygen were collected. By calculating the areas under the receiver-operating characteristic curves (AUC), we compared the performance of blood laboratory-arterial gas analyses features alone and combined with the CT features in two hybrid models (Hybrid radiological and Hybrid radiomics)for predicting ICU admission. Following a machine learning approach, 63 patients were allocated to the training and 52 to the validation set. Twenty-nine (25%) of patients were admitted to ICU. The Hybrid radiological model comprising the lung %consolidation performed significantly (p = 0.04) better in predicting ICU admission in the validation (AUC = 0.82; 95% confidence interval 0.73-0.97) set than the blood laboratory-arterial gas analyses features alone (AUC = 0.71; 95% confidence interval 0.56-0.86). A risk calculator for ICU admission was derived and is available at: https://github.com/cgplab/covidapp . The volume of the consolidated lung in CT of patients with COVID-19 pneumonia has a mild but significant incremental value in predicting ICU admission.

Increased Creatine Kinase May Predict A Worse COVID-19 Outcome.

Early reports from Asia suggested that increased serum levels of the muscular enzyme creatine-(phospho)-kinase (CK/CPK) could be associated with a more severe prognosis in COVID-19. The aim of this single-center retrospective cohort study of 331 consecutive COVID-19 patients who were hospitalized during Italy's "first wave" was to verify this relationship, and to evaluate the role of possible confounding factors (age, body mass index, gender, and comorbidities). We subdivided our cohort in two groups, based on "severe" (n = 99) or "mild" (n = 232) outcomes. "Severe" disease is defined here as death and/or mechanical invasive ventilation, in contrast to "mild" patients, who were discharged alive with no need for invasive ventilation; this latter group could also include those patients who were treated with non-invasive ventilation. The CK levels at admission were higher in those subjects who later experienced more severe outcomes (median, 126; range, 10-1672 U/L, versus median, 82; range, 12-1499 U/L, p = 0.01), and hyperCKemia >200 U/L was associated with a worse prognosis. Regression analysis confirmed that increased CK acted as an independent predictor for a "severe" outcome. HyperCKemia was generally transient, returning to normal during hospitalization in the majority of both "severe" and "mild" patients. Although the direct infection of voluntary muscle is unproven, transient muscular dysfunction is common during the course of COVID-19. The influence of this novel coronavirus on voluntary muscle really needs to be clarified.

Switch to maraviroc with darunavir/r, both QD, in patients with suppressed HIV-1 was well tolerated but virologically inferior to standard antiretroviral therapy: 48-week results of a randomized trial.

OBJECTIVES: Primary study outcome was absence of treatment failure (virological failure, VF, or treatment interruption) per protocol at week 48. METHODS: Patients on 3-drug ART with stable HIV-1 RNA <50 copies/mL and CCR5-tropic virus were randomized 1:1 to maraviroc with darunavir/ritonavir qd (study arm) or continue current ART (continuation arm). RESULTS: In June 2015, 115 patients were evaluable for the primary outcome (56 study, 59 continuation arm). The study was discontinued due to excess of VF in the study arm (7 cases, 12.5%, vs 0 in the continuation arm, p = 0.005). The proportion free of treatment failure was 73.2% in the study and 59.3% in the continuation arm. Two participants in the study and 10 in the continuation arm discontinued therapy due to adverse events (p = 0.030). At VF, no emergent drug resistance was detected. Co-receptor tropism switched to non-R5 in one patient. Patients with VF reported lower adherence and had lower plasma drug levels. Femoral bone mineral density was significantly improved in the study arm. CONCLUSION: Switching to maraviroc with darunavir/ritonavir qd in virologically suppressed patients was associated with improved tolerability but was virologically inferior to 3-drug therapy.

Streptococcus agalactiae: prevalence of antimicrobial resistance in vaginal and rectal swabs in Italian pregnant women.

Intrapartum antibiotic prophylaxis (IAP) reduces both the vertical transmission of Streptococcus agalactiae or Group B Streptococcus (GBS) and the early onset of neonatal sepsis. However, existing guidelines do not recommend that antimicrobial susceptibility testing (AST) be routinely performed. Penicillin or ampicillin are indicated as first-choice antibiotics, cefazolin being an alternative in the case of history of mild allergic reactions, and vancomycin or clindamycin an alternative in the event of severe reactions. We performed a cross-sectional analysis to identify the presence of any bacterial resistance towards the antibiotics most frequently used for IAP in pregnant women with GBS positive vaginal-rectal swabs, in the Pistoia area of central Italy. Of the 255 tested samples, 65 (25.5%) were positive for GBS. Sensitivity to glycopeptides was over 90%, but lower to ampicillin and penicillin (87.10% and 87.93% respectively). Resistance towards clindamycin and erythromycin was as high as 43.75% and 32.20%. All tested GBS proved susceptible to moxifloxacin, linezolid and tigecycline. Our observed prevalence is aligned or slightly higher than data reported in other series. The less than full effectiveness and low percentages of ampicillin and penicillin sensitivity observed give cause for concern. We confirmed the increase in clindamycin and erythromycin resistance. Glycopeptides can be used as second-line antibiotics, but the complete AST of GBS should always be performed before IAP. Given that gentamicin is used synergically with penicillin when treating chorioamnionitis, it needs to be always included in the AST. This is the first study on the GBS sensitivity profile in Tuscany. Further investigation on a larger scale is required prior to implementing any changes in the current guidelines.

Cost of HAART in Italy: multicentric evaluation and determinants from a large HIV outpatient cohort.

BACKGROUND: As HIV infection turned into a chronic treatable disease, now ranking as one of the most costly in medicine, long-term sustainability of highly active antiretroviral treatment (HAART) expenses became a major issue, especially in countries with universal access to care. Identification of determinants of higher HAART costs may therefore help in controlling costs of care, while keeping high levels of retention in care and viral suppression. METHODS: With this aim, we enrolled a large multicentric sample of consecutive unselected human immunodeficiency virus (HIV) patients followed at five sites of care in Italy, and evaluated annual individual HAART costs in relation to a number of sociodemographic, clinical, and laboratory variables. RESULTS: We enrolled 2,044 patients, including 1,902 on HAART. Mean HAART costs were €9,377±€3,501 (range 782-29,852) per year, with remarkable site-based differences, possibly related to the different composition of local assisted populations. Percentages of patients on viral suppression were homogeneously high across all study sites. The factors identified by cross-validation were line of HAART, diagnosis of acquired immune deficiency syndrome, current CD4 T-cell count, and detectable HIV viremia >50 copies/mL. In the final multivariable model, HAART costs were independently directly associated with more advanced HAART line (P<0.001) and inversely correlated with current CD4 T-cell count (P=0.024). Site of care held independent prediction of higher costs, with marked control of expenses at sites 2 (P=0.001) and 5 (P<0.001). CONCLUSION: Higher costs of HAART were strongly associated with previous treatment failures, detectable HIV viremia, and lower CD4 T-cell count at the time of evaluation, with no correlation at all with sex, age, hepatitis C virus coinfection, and nadir CD4 T-cell counts. Newer drugs, which are typically those associated with high prices, at the time of the analysis were still prevalently prescribed to rescue and maintain viral suppression in patients with more complex treatment history. Further analyses of the contribution of the single drug/regimen to the estimated cost are warranted.

Four years data of raltegravir-based salvage therapy in HIV-1-infected, treatment-experienced patients: the SALIR-E Study.

Apart from the BENCHMRK study, there are no large observational experiences describing the long-term efficacy and safety of rescue regimens for human immunodeficiency virus type 1 (HIV-1) infection. Antiretroviral-experienced patients with detectable viraemia starting a raltegravir (RAL)-based regimen between March 2007 and June 2009 were consecutively enrolled and followed for ≥4 years. Data were censored at Week 206 for homogeneity. Of 333 patients, 258 (77.5%) were still on RAL-based therapy at Week 206, and 241 had undetectable HIV-1 RNA (73% in intention-to-treat analysis). Of the 75 subjects who discontinued RAL therapy, 36 were lost to follow-up, 15 changed their regimen due to virological failure, 2 simplified their regimen stopping RAL, 9 stopped all antiretrovirals and 13 died. Overall, 100 subjects (30.0%) had at least one detectable viraemia, but only 32 (9.6%) had true viral failure. Seventeen patients continued their failing regimen. 'Blips' were experienced by 53 patients (15.9%), whilst 15 (4.5%) had confirmed viral rebound due to adherence issues and were re-suppressed upon treatment re-introduction. In a multivariate analysis of predictors of interruption or failure, each baseline HIV-1 RNA log10 increase was associated with an adjusted hazard ratio for failure of 1.6; having more than 13 previous treatment courses also emerged as a predictor. Overall, adverse events were rare (n=64), with 13 deaths. Tumours were mainly early events, often fatal (7/15), mainly non-Hodgkin's lymphomas (8), followed by hepatocarcinoma (2). RAL proved effective and well tolerated in this cohort, and few patients experienced viral failure after 4 years.

96 Week follow-up of HIV-infected patients in rescue with raltegravir plus optimized backbone regimens: a multicentre Italian experience.

BACKGROUND: Long term efficacy of raltegravir (RAL)-including regimens in highly pre-treated HIV-1-infected patients has been demonstrated in registration trials. However, few studies have assessed durability in routine clinical settings. METHODS: Antiretroviral treatment-experienced patients initiating a RAL-containing salvage regimen were enrolled. Routine clinical and laboratory follow-up was performed at baseline, week 4, 12, and every 12 weeks thereafter. Data were censored at week 96. RESULTS: Out of 320 patients enrolled, 292 (91.25%) subjects maintained their initial regimen for 96 weeks; 28 discontinued prematurely for various reasons: death (11), viral failure (8), adverse events (5), loss to follow-up (3), consent withdrawal (1). Eight among these 28 subjects maintained RAL but changed the accompanying drugs. The mean CD4+ T-cell increase at week 96 was 227/mm(3); 273 out of 300 patients (91%), who were still receiving RAL at week 96, achieved viral suppression (HIV-1 RNA <50 copies/mL). When analyzing the immuno-virologic outcome according to the number of drugs used in the regimen, 2 (n = 45), 3 (n = 111), 4 (n = 124), or >4 (n = 40), CD4+ T-cell gain was similar across strata: +270, +214, +216, and +240 cells/mm(3), respectively, as was the proportion of subjects with undetectable viral load. Laboratory abnormalities (elevation of liver enzymes, total cholesterol and triglycerides) were rare, ranging from 0.9 to 3.1%. The mean 96-week total cholesterol increase was 23.6 mg/dL. CONCLUSIONS: In a routine clinical setting, a RAL-based regimen allowed most patients in salvage therapy to achieve optimal viral suppression for at least 96 weeks, with relevant immunologic gain and very few adverse events.

Evolution and predictors of HIV type-1 drug resistance in patients failing combination antiretroviral therapy in Italy.

BACKGROUND: This study aimed to examine the evolution of genotypic drug resistance prevalence in treatment-failing patients in the multicentre, Italian, Antiretroviral Resistance Cohort Analysis (ARCA). METHODS: Patients with a drug resistance genotype test performed between 1999 and 2006 at failure of a combination antiretroviral therapy and with complete treatment history were selected. The prevalence of resistance was measured overall, per calendar year, per drug class and per treatment line at failure. RESULTS: The overall resistance prevalence was 81%. Resistance to nucleoside reverse transcriptase inhibitors (NRTIs) declined after 2002 (68% in 2006; chi(2) for trend P=0.004); resistance to non-NRTIs (NNRTIs) stabilized after 2004; and resistance to protease inhibitors (PIs) declined after 2001 (43% in 2006; P=0.004). In first-line failures, NRTI resistance decreased after 2002 (P=0.006), NNRTI resistance decreased after 2003 (P=0.001) and PI resistance decreased after 2001 (P<0.001). Independent predictors of resistance to any class were HIV type-1 transmission by heterosexual contacts as compared with injecting drug use, a higher number of experienced regimens, prior history of suboptimal therapy, higher viral load and CD4+ T-cell counts, more recent calendar year and viral subtype B carriage, whereas the use of PI-based versus NNRTI-based regimens at failure was associated with a reduced risk of resistance. There was an increase of type-1 thymidine analogue and of protease mutations L33F, I47A/V, I50V and I54L/M, whereas L90M decreased over calendar years. CONCLUSIONS: During more recent years, emerging drug resistance has decreased, particularly in first-line failures. The prevalence continues to be high in multiregimen-failing patients.