Dolutegravir Discontinuation for Neuropsychiatric Symptoms in People Living with HIV and Their Outcomes after Treatment Change: A Pharmacogenetic Study.

Neuropsychiatric symptoms have been reported in patients receiving dolutegravir, a known inhibitor of the renal and neuronal-expressed organic anion transporter 2 (encoded by SLC22A2 gene). The effect of the genetic variant SLC22A2 808C>A on dolutegravir discontinuation was assessed and analyzed by real-time PCR. We enrolled 627 participants: CA/AA carriers showed a higher prevalence of pre-existing psychiatric comorbidities and use of antidepressants. After 27.9 months, 108 participants discontinued dolutegravir, 64 for neuropsychiatric symptoms. Patients with pre-existing psychiatric comorbidities were at higher risk of dolutegravir discontinuation, while patients carrying the SLC22A2 CA/AA genotype were not. Combining the two variables, an opposite effect of SLC22A2 variants according to pre-existing psychiatric disorders was observed. Using multivariate Cox models, the combined variable pre-existing psychiatric comorbidities/SLC22A2 variants and the use of non-tenofovir alafenamide containing antiretroviral regimens were predictors of dolutegravir discontinuation for neuropsychiatric symptoms. Within 30 days, the majority of participants had a complete resolution of symptoms (61.8%), while 32.7% and 5.5% had partial or no change after dolutegravir discontinuation, respectively. Discontinuation of dolutegravir for neuropsychiatric symptoms was not uncommon and more frequent in participants with pre-existing psychiatric disorders. We described an interaction between SLC22A2 genetic variant and psychiatric comorbidities. In 38.2% of patients, a complete neuropsychiatric symptoms resolution was not observed after dolutegravir discontinuation suggesting the involvement of additional factors.

Screening Accuracy of Mini Addenbrooke's Cognitive Examination Test for HIV-Associated Neurocognitive Disorders in People Ageing with HIV.

Aging and increased cardiovascular risk are major drivers for HIV-associated neurocognitive disorders (HAND), for which accurate screenings are lacking. Mini-Addenbrooke's Cognitive Examination (MACE) reliably detects vascular and neurodegenerative cognitive decline among HIV-negative patients. We evaluated MACE diagnostic accuracy in detecting HAND in people living with HIV (PLWH) and we compared it with the International HIV Dementia Scale (IHDS). A single-centre double-blind study of diagnostic accuracy on adult outpatient PLWH without neurocognitive confounding was performed. MACE and IHDS were administered in 5 and 10 min by clinicians, followed by the reference standard battery (14 tests) by neuropsychologists. HAND diagnosis was based on the modified version of Frascati's criteria by Gisslén to reduce false positives. Exploratory cut-offs were evaluated for MACE. Diagnostic accuracy and clinical utility parameters were assessed. 231 patients were enrolled. 75.7% men with a median age, education, and length of infection of 54 (48-59), 10 (8-13) and 16 (5-25) years. HAND prevalence was 48.5% (38.9% asymptomatic impairment). Compared to IHDS, MACE sensitivity (89.3% vs 70.5%), specificity (94.1% vs 63.0%), correct classification rate (86.5% vs 66.7%), J index (0.83 vs 0.34), AUROC (0.97 vs 0.79), agreement with the gold standard (k 0.84 vs 0.33) and effect size in distinguishing HAND vs non-HAND (d 2.11 vs 1.15) were higher. Among PLWH aged 65 years and above (n = 37) MACE performance was consistently better than IHDS. The quick and easy-to-perform MACE could possess an accurate and useful screening performance for HAND in otherwise neurocognitively healthy cohorts of PLWH.

Effectiveness of a screening program for HBV, HCV, and HIV infections in African migrants to Sicily.

BACKGROUND: Migrants from Africa are vulnerable to viral infections during their journey. METHODS: Migrants who arrived in western Sicily were offered early screening for hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) infection. A questionnaire was administered to evaluate risk factors, and antiviral therapy was offered to subjects with active infection. A multiple regression analysis and adjusted odds ratio were obtained to evaluate risk factors. RESULTS: Overall, 2,639 of 2,751 (95.9%) migrants who arrived between 2015 and 2017 accepted screening and 1,911 (72.4%) completed the questionnaire. HBsAg was positive in 257 (9.7%) migrants, 24 (0.9%) were anti-HCV positive and 57 (2.2%) had HIV infection. The prevalence of HBV infection was higher in women (aOR 2.47,95%CI 1.90-3.20),p = 0.003) and in people who endured physical and/or sexual violence (aOR 2.24,95%CI 1.87-3.55,p<0.001), while HIV infection was more frequent in women (aOR 5.40,95%CI 3.09-9.43, p <0.001) who were in Libya for a long period (aOR 5.66,95%CI 2.90-10.70,p = 0.004) and endured physical and/or sexual violence (aOR 14.77,95%CI 8.34-22.11,p<0.001). Being older than 18 was associated with HCV infection (p<0.001). Overall, 77% of 57 subjects with HIV infection were retained in care, 79% of 70 chronic HBV hepatitis cases started nucleot(s)ide analogues and 61% of 18 HCV-RNA positive cases received direct-acting antiviral therapy. CONCLUSIONS: These findings evidence the effectiveness and feasibility of infectious disease screening programs for migrants.

Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.

Importance: The coronavirus disease 2019 (COVID-19) pandemic is threatening billions of people worldwide. Tocilizumab has shown promising results in retrospective studies in patients with COVID-19 pneumonia with a good safety profile. Objective: To evaluate the effect of early tocilizumab administration vs standard therapy in preventing clinical worsening in patients hospitalized with COVID-19 pneumonia. Design, Setting, and Participants: Prospective, open-label, randomized clinical trial that randomized patients hospitalized between March 31 and June 11, 2020, with COVID-19 pneumonia to receive tocilizumab or standard of care in 24 hospitals in Italy. Cases of COVID-19 were confirmed by polymerase chain reaction method with nasopharyngeal swab. Eligibility criteria included COVID-19 pneumonia documented by radiologic imaging, partial pressure of arterial oxygen to fraction of inspired oxygen (Pao2/Fio2) ratio between 200 and 300 mm Hg, and an inflammatory phenotype defined by fever and elevated C-reactive protein. Interventions: Patients in the experimental arm received intravenous tocilizumab within 8 hours from randomization (8 mg/kg up to a maximum of 800 mg), followed by a second dose after 12 hours. Patients in the control arm received supportive care following the protocols of each clinical center until clinical worsening and then could receive tocilizumab as a rescue therapy. Main Outcome and Measures: The primary composite outcome was defined as entry into the intensive care unit with invasive mechanical ventilation, death from all causes, or clinical aggravation documented by the finding of a Pao2/Fio2 ratio less than 150 mm Hg, whichever came first. Results: A total of 126 patients were randomized (60 to the tocilizumab group; 66 to the control group). The median (interquartile range) age was 60.0 (53.0-72.0) years, and the majority of patients were male (77 of 126, 61.1%). Three patients withdrew from the study, leaving 123 patients available for the intention-to-treat analyses. Seventeen patients of 60 (28.3%) in the tocilizumab arm and 17 of 63 (27.0%) in the standard care group showed clinical worsening within 14 days since randomization (rate ratio, 1.05; 95% CI, 0.59-1.86). Two patients in the experimental group and 1 in the control group died before 30 days from randomization, and 6 and 5 patients were intubated in the 2 groups, respectively. The trial was prematurely interrupted after an interim analysis for futility. Conclusions and Relevance: In this randomized clinical trial of hospitalized adult patients with COVID-19 pneumonia and Pao2/Fio2 ratio between 200 and 300 mm Hg who received tocilizumab, no benefit on disease progression was observed compared with standard care. Further blinded, placebo-controlled randomized clinical trials are needed to confirm the results and to evaluate possible applications of tocilizumab in different stages of the disease. Trial Registration: ClinicalTrials.gov Identifier: NCT04346355; EudraCT Identifier: 2020-001386-37.

Older Age is Associated with Higher Dolutegravir Exposure in Plasma and Cerebrospinal Fluid of People Living with HIV.

BACKGROUND: People living with human immunodeficiency virus are ageing under combination antiretroviral treatments but data on drug exposure in serum and cerebrospinal fluid are limited. Dolutegravir is a widely used second-generation integrase strand transfer inhibitor: conflicting data suggest that neuropsychiatric side effects may present at a higher frequency in patients with higher dolutegravir serum concentrations. METHODS: We performed a retrospective analysis of our therapeutic drug monitoring registry identifying patients receiving once-daily dolutegravir without concomitant interacting drugs and significant clinical conditions. Data were analysed stratifying time after drug dose intake (maximum concentration 0.5-4 and trough concentration 21-27 h). Cerebrospinal fluid samples from patients enrolled in neurological studies and receiving dolutegravir were analysed for dolutegravir cerebrospinal fluid concentrations and cerebrospinal fluid-to-plasma ratios. Serum and cerebrospinal fluid concentrations were measured through validated chromatographic methods. RESULTS: We included 207 (providing 457 serum samples) and 41 patients (providing 41 cerebrospinal fluid samples). Participants were mostly male (68.2-72.8%) of median age of 50 years (50-53 years). Non-significant changes in dolutegravir maximum concentration and trough concentration were observed with age at Spearman's test (p values > 0.05); linear logistic regression showed a significant effect of age on dolutegravir trough concentration (p = 0.0013) (Fig. 1). Dolutegravir maximum concentration [3830 ng/mL (2311-5057) vs 4230 ng/mL (2919-5272), p = 0.311] and trough concentration [838 ng/mL (362-1587) vs 966 ng/mL (460-2085), p = 0.056] were non-significantly or borderline higher in patients aged > 50 years. Cerebrospinal dolutegravir concentrations were associated with plasma concentrations (ρ = 0.374, p = 0.016) and age (ρ = 0.537, p = 0.003); cerebrospinal fluid dolutegravir concentrations (13.8 vs 7.3 ng/mL, p = 0.015) and cerebrospinal fluid-to-plasma ratios (0.57 vs 0.32%, p = 0.017] were higher in participants aged > 50 years. CONCLUSIONS: We observed an increase in dolutegravir exposure in serum and in cerebrospinal fluid in older patients living with human immunodeficiency virus.

Urinary schistosomiasis in migrant population: a case series from a single centre in southern Italy.

PURPOSE: To understand the frequency of urinary schistosomiasis, in migrants in clinical follow-up at the infectious disease outpatient clinic of ARNAS Civico Hospital in Palermo Italy, to raise awareness on this neglected tropical disease. METHODS: A retrospective analysis of migrant patients in clinical care in our centre during the triennium 2015-2017. RESULTS: 2639 migrants have been in clinical care during the triennium 2015-2017, 72% are male and 28% are female. 214 patients were tested for the presence of Schistosoma eggs in urine, these patients are all male. All the patients tested, reported macroscopic haematuria and the 54% had an increase in the peripheral blood eosinophil count. Ninety subjects had a positive microscopic examination for Schistosoma haematobium eggs. Patients were treated with a standard dose of praziquantel (40 mg/kg), and tested for Schistosoma 1 month after the end of therapy. All the subjects fully recovered. CONCLUSIONS: Considering the migration phenomenon, the observation of these tropical diseases in European hospitals is becoming more and more common and an increasing number of health care professionals will be dealing with migrants. Searching for haematuria and eosinophilia and then testing for Schistosoma in this specific population will increase the number of diagnosis and correct treatment of urinary schistosomiasis, improving the patients' quality of life and preventing severe complications of the disease.