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Objective(s) This prospective observational cohort study aimed to evaluate whether women with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the first trimester of pregnancy are at higher risk of adverse obstetric and neonatal outcomes compared to negative patients. Study design Seromolecular testing for SARS-CoV-2 was performed at 12, 16, 21 weeks, and at delivery; the cohort was then subdivided into a first-trimester SARS-CoV-2-positive (case) group and a SARS-CoV-2-negative (control) group. The primary outcome was a composite adverse obstetric outcome, defined as the presence of either abortion, preterm delivery, preterm prelabor rupture of membranes, preeclampsia, intrauterine growth restriction, stillbirth; and a composite measure of adverse neonatal events, including either 1- and 5-min Apgar score ≤ 7, neonatal intensive care unit admission and congenital birth defects. Maternal symptoms and antibody titer were secondarily assessed. Results A total of 17 of 164 women tested positive for SARS-CoV-2 (10.3%) in the first trimester. One SARS-CoV-2-positive patient who gave birth at another hospital was excluded. Composite adverse obstetric outcome was observed in 6.2% (1/16) SARS-CoV-2-positive and 10.5% (11/105) SARS-CoV-2-negative women; composite adverse neonatal outcome in 12.5% (2/16) and 7.6% (8/105), respectively. In the newborns of women who had developed IgG antibodies, the same antibodies were detected in arterial cord blood and the nasopharyngeal swab tested negative for SARS-CoV-2. No maternal pneumonia or hospital admission due to coronavirus disease-19 were recorded. Conclusion Asymptomatic or mildly symptomatic women during the first trimester of pregnancy did not experience significantly more adverse events than SARS-CoV-2-negative women.

Remdesivir is one of the most encouraging treatments against SARS‐CoV‐2 infection. After intravenous infusion, RDV is rapidly metabolized (T1/2 1h) within the cells to its active adenosine triphosphate analogue form (GS‐443902) and, then, it can be found in plasma in its nucleoside analogue form (GS‐441524). In this real life study we describe the Remdesivir and GS‐441524 concentrations at 3 time points in nine ICU patients, through a validated UHPLC‐MS/MS method. The observed data confirmed the very rapid conversion of RDV to its metabolite and the quite long half‐life of GS‐441524. The mean C min, C max, AUC0–24, were < 0.24 ng/mL and 122.3 ng/ml, 2637,3 ng/mL and 157,8 ng/ml, 5171.2 ng*h/mL and 3676.5 ng*h/ml respectively for RDV and GS‐441524. Three out of nine patients achieved a C max> 2610 ng/mL and 140 ng/mL and AUC0–24 > 1560 ng*h/mL and 2230 ng*h/mL for RDV and GS‐441524, respectively. The mean T1/2 value for GS‐441524 was 26.3 h. Although the low number of patients, these data can represent an interesting preliminary report of the variability of RDV and GS‐441524 concentrations in real‐life ICU setting.

Introduction: In Italy, hepatitis C virus (HCV) elimination is achievable; however, barriers remain to achieving the World Health Organization's elimination targets, and have become more pronounced with the spread of COVID-19. Glecaprevir/pibrentasvir (G/P) is a direct-acting antiviral therapy for HCV, approved for 8-week treatment in patients without cirrhosis, and with compensated cirrhosis (CC). Previously, 12 weeks of therapy was recommended for patients with CC. Shortened treatment may reduce the burden on healthcare resources, allowing more patients to be treated. This study presents the benefits that 8-week vs 12-week treatment with G/P may have in Italy. Methods: A multicohort Markov model was used to assess the collective number of healthcare visits and time on treatment with 8-week vs 12-week G/P in the HCV-infected population of Italy from 2019 to 2030, using healthcare resource data from post-marketing observational studies of G/P. Increased treatment capacity and downstream clinical and economic benefits were also assessed assuming the reallocation of saved healthcare visits to treat more patients. Results: Modeled outcomes showed that by 2030, 8-week treatment saved 27,006 years on therapy compared with 12-week treatment, with 21,065 fewer hepatologist visits. Reallocating these resources to treat more patients could increase capacity to treat 5064 (1.4%) more patients with 8 weeks of G/P, all with CC. This increased treatment capacity would further avoid 2257 cases of end-stage liver disease, 893 liver-related deaths, and provide net savings to the healthcare system of nearly €70 million. Conclusion: The modeled comparisons between 8- and 12-week treatment with G/P show that shorter treatment duration can lead to greater time and resource savings, both in terms of healthcare visits and downstream costs. These benefits have the potential to enable the treatment of more patients to overcome elimination barriers in Italy through programs aimed to engage and treat targeted HCV populations.

Objective The aim of this study was to explore weight gain in people with HIV (PWH) at least 65 years of age who switch to a DTG based regimen (DTG-s) vs. remaining INSTI-naive (INSTI-n) on stable ART. Methods This was a longitudinal prospective study of PWH from the GEPPO cohort. At the beginning of the observational period, participants were INSTI-naives (INSTI-n). During follow-up, they were divided in two groups: INSTI-n vs. dolutegravir-switchers (DTG-s) with no further change in ART. Body weight was assessed at baseline and at last follow-up visit. Significant weight gain was defined as an increase at least 5% of baseline weight from the first to the last visit. ART regimens were collected at each patients' visit. Kaplan--Meier curves were drawn to assess time to reach a weight gain more than 5%. Results Out of 568 PWH (83.1% men, median age 69.5 years), 427 (75%) were INSTI-n and 141 (25%) DTG-s. After an average follow-up of 2.6 (±0.8) years, no significant change in body weight was observed both among INSTI-n [delta weight = 0.02 (±7.5), P = 0.633] and DTG-s [delta weight = -0.04 (±5.2), P = 0.755]. Weight gain was also not significantly different between study groups (9.3% in INSTI-n and 15.1% in DTG-S: P = 0.175). No significant differences in time to achieve a weight gain greater or equal than 5% of baseline weight emerged in INSTI-n vs. DTG-s (P = 0.93), two-drug regimens (2DR) vs. three-drug regimens (3DR) (P = 0.56) or TAF vs. TDF (P = 0.56). Conclusion Results from a large Italian cohort did not show a significant weight gain associated with switch to DTG in PWH 65 years of age or older. This finding emerged also when comparing 3DR vs. 2DR and TAF exposed and unexposed geriatric PWH.

Congenitally- or perinatally-acquired viral infections can be harmful to the fetus but data are limited about prevalence and outcomes of coronavirus disease 2019 (COVID-19) disease during the first trimester of pregnancy. We report epidemiologic data from a study investigating a cohort of women who became pregnant just before or during the COVID-19 pandemic. We recruited 138 consecutive pregnant women attending for first trimester screening (11-13 weeks of gestation) at Sant'Anna Hospital, Turin, Piedmont, Italy, during the plateau and the falling phase of the COVID-19 epidemic curve. Patients were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin M/immunoglobulin G antibody levels and SARS-CoV-2 detection in sera and nasopharyngeal swab samples. COVID-19 cumulative incidence during the first trimester was of 10.1% with high prevalence of asymptomatic patients (42.8%). Similar to the course of the disease in non pregnant adults, 80% to 90% of infections were not severe.The prevalence of reported symptoms was four-fold higher in SARS-CoV-2 positive patients (57%) than in those negative (13%) (P < .001), suggesting that direct self-testing should open doors to confirmatory testing for COVID-19. Our findings support the need for COVID-19 screening in early pregnancy in epidemic areas to plan materno-fetal health surveillance programs.

Objectives Following the public-health emergency of international concern (PHEIC) declared by the World Health Organization (WHO) on 30 January 2020 and the recent outbreak caused by 2019 novel coronavirus (2019-nCoV) [officially renamed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)] in China and 29 other countries, we aimed to summarise the clinical aspects of the novelBetacoronavirus disease (COVID-19) and its possible clinical presentations together with suggested therapeutic algorithms for patients who may require antimicrobial treatment. Methods The currently available literature was reviewed for microbiologically confirmed infections by 2019-nCoV or COVID-19 at the time of writing (13 February 2020). A literature search was performed using the PubMed database and Cochrane Library. Search terms included ‘novel coronavirus’ or ‘2019-nCoV’ or ‘COVID-19’. Results Published cases occurred mostly in males (age range, 8–92 years). Cardiovascular, digestive and endocrine system diseases were commonly reported, except previous chronic pulmonary diseases [e.g. chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis] that were surprisingly underreported. Fever was present in all of the case series available, flanked by cough, dyspnoea, myalgia and fatigue. Multiple bilateral lobular and subsegmental areas of consolidation or bilateral ground-glass opacities were the main reported radiological features of 2019-nCoV infection, at least in the early phases of the disease. Conclusion The new 2019-nCoV epidemic is mainly associated with respiratory disease and few extrapulmonary signs. However, there is a low rate of associated pre-existing respiratory co-morbidities.

The presence of psychiatric disorders (PD) in patients affected by chronic hepatitis C (CHC) was a major contraindication for the treatment with interferon (IFN)-based regimens. The novel IFN-free approach using the direct-acting antiviral agents (DAAs) is an interesting and promising chance for these subjects. In this retrospective analysis we focused the attention on the virological response and safety of CHC patients affected by PD and treated with IFN-free regimens. 136 subjects were enrolled in this study. Treatment naive were 78 (57.3), experienced 58 (42.6%). Major depression was present in 25 patients (18.4%), anxiety disorders in 37 (27.2%), bipolar disorders in 23 (16.9%), schizophrenia in 17 (12.5%), behavioral disturbance in 21 (15.4%), psychosis in 13 (9.5%). Psychoactive medication taken by patients were: benzodiazepines (n = 29, 21.3%), antidepressants (n = 24, 17.6%), neuroleptics (n = 29, 21.3%), mood stabilizers (n = 19, 14%), combinations of different drugs (n = 17, 12.5%). Sustained virological response at 12 weeks of follow-up (SVR12) was observed in 128 patients (94.1%), drop-out were 3 (2.2%). No adverse events or significant drug-related side-effects were reported. The treatment with novel IFN-free therapies against CHC were higher effective and well tolerated also in patients with PD taking psychoactive medications.

Background Tuberculous meningitis (TBM) is an important disease leading to morbidity, disability and mortality that primarily affects children and immune-depressed patients. Specific neuromarkers predicting outcomes, severity and inflammatory response are still lacking. In recent years an increasing number of evidences show a possible role for infective agents in developing neurodegenerative diseases. Methods We retrospectively included 13 HIV-negative patients presenting with TBM and we compared them with two control groups: one of patients with a confirmed diagnosis of AD, and one of those with syphilis where lumbar punctures excluded central nervous system involvement. Lumbar punctures were performed for clinical reasons and CSF biomarkers were routinely available: we analyzed blood brain barrier permeability (CSF to serum albumin ratio, “CSAR”), intrathecal IgG synthesis, (CSF to serum IgG ratio), inflammation (neopterin), amyloid deposition (Aβ1–42), neuronal damage (T-tau, P-tau, 14.3.3) and astrocytosis (S-100 β). Results TBM patients were 83 % male and 67 % Caucasian with a median age of 51 years (24.5–63.5 IQR). Apart from altered CSAR (median value 18.4, 17.1–30.9 IQR), neopterin (14.3 ng/ml, 9.7–18.8) and IgG ratios (15.4, 7.9–24.9), patients showed very low levels of Aβ1–42 in their CSF (348.5 pg/mL,125-532.2), even lower compared to AD and controls [603 pg/mL (IQR 528–797) and 978 (IQR 789–1178)]. Protein 14.3.3 tested altered in 38.5 % cases. T-tau, P-tau and S100Beta were in the range of normality. Altered low level of Aβ1–42 correlated over time with classical TBM findings and altered neuromarkers. Conclusions CSF Biomarkers from patients with TBM were compatible with inflammation, blood brain barrier damage and impairment in amyloid-beta metabolism. Amyloid-beta could be tested as a prognostic markers, backing the routine use of available neuromarkers. To our knowledge this is the first case showing such low levels of Aβ1–42 in TBM; its accumulation, drove by neuroinflammation related to infections, can be central in understanding neurodegenerative diseases.

We measured severe acute respiratory syndrome coronavirus 2 spike protein subunits S1/S2 antibodies by using capillary electrophoresis and a chemiluminescence immunoassay for 5,444 active healthcare workers in Italy. Seroprevalence was 6.9% and higher among participants having contact with patients. Seroconversion was not observed in 37/213 previously infected participants.

Although studies show an annual trend for immunosuppressive drugs, particularly during different seasons, no data are available for antiretroviral drugs exposures in different periods of the year. For this reason, the aim of this study was to investigate an association between seasonality and antiretroviral drugs plasma concentrations. Antiretroviral drugs exposures were measured with liquid chromatography validated methods. A total of 4148 human samples were analysed. Lopinavir, etravirine and maraviroc levels showed seasonal fluctuation. In detail, maraviroc and etravirine concentrations decreased further in summer than in winter. In contrast, lopinavir concentrations had an opposite trend, increasing more in summer than in winter. The etravirine efficacy cut-off value of 300 ng/mL seems to be affected by seasonality: 77.1% and 22.9% of samples achieved this therapeutic target, respectively, in winter and summer, whereas 30% in winter and 70% in summer did not reach this value. Finally, age over 50 years and summer remained in the final multivariate regression model as predictors of the etravirine efficacy cut-off. This study highlights the seasonal variation in antiretroviral drugs plasma concentrations during the year, leading to a better understanding of inter-individual variability in drug exposures. Studies are required in order to confirm these data, clarifying which aspects may be involved.

Pathocoenosis and syndemics theories have emerged in the last decades meeting the frequent need of better understanding interconnections and reciprocal influences that coexistent communicable and non-communicable diseases play in a specific population. Nevertheless, the attention to pharmacokinetic and pharmacodynamics interactions of co-administered drugs for co-present diseases is to date limitedly paid to alert against detrimental pharmacological combos. Low and middle-income countries are plagued by the highest burden of HIV, tuberculosis, malaria, and helminthiasis, and they are experiencing an alarming rise in non-communicable disorders. In these settings, co-infections and comorbidities are common, but no tailored prescribing nor clinical trials are used to assess and exploit existing opportunities for the simultaneous and potentially synergistic treatment of intertwined diseases. Pharmacoenosis is the set of interactions that take place within a host as well as within a population due to the compresence of two or more diseases and their respective treatments. This framework should pilot integrated health programmes and routine clinical practice to face drug–drug interaction issues, avoiding negative co-administrations but also exploiting potential favourable ones to make the best out of the worst situations; still, to date, guiding data on the latter possibility is limited. Therefore, in this narrative review, we have briefly described both detrimental and favourable physiopathological interactions between HIV and other common co-occurring pathologies (malaria, tuberculosis, helminths, and cardiovascular disorders), and we have presented examples of advantageous potential pharmacological interactions among the drugs prescribed for these diseases from a pharmacokinetics, pharmacodynamics, and pharmacogenetics standpoint.

The aim of this study was the evaluation of plasmatic and urinary therapeutic drug monitoring (TDM) of tenofovir disoproxil fumarate (TDF) in a cohort of patients affected by chronic hepatitis B (CHB). In 68 enrolled patients eGFR was 68 ml/min in naive, while in adefovir dipivoxil (ADV) pretreated patients was 55.5 ml/min (ppp

Background Antiviral and immune-modulating properties of low-molecular-weight heparin (LMWH) against Coronaviridae have been reported by in vitro studies, but no in vivo evidence is yet available. We sought to know whether the timing of prophylactic doses of LMWH during the course of COVID-19 may affect the time to SARS-CoV-2 nasal-oropharyngeal swab negativization. Methods Retrospective monocentric cross-sectional study on patients requiring sub-intensive ward admission due to first SARS-CoV-2 infection and undergoing early (EH; within 7 days from COVID-19 signs and symptoms onset) versus delayed prophylactic LMWH (DH; after 7 days). SARS-CoV-2 RNA was measured by reverse transcription real-time PCR according to scheduled time points: first swab after 2 weeks from COVID-19 onset, then at 1-week intervals until negativity. Results Time to SARS-CoV-2 swab negativity was shorter in EH (38 patients) compared with DH (55 patients): 22 versus 37 days ( P=0.004). The number of confirmative negative swabs in EH was significantly higher compared with DH at week 2 (21.1% versus 3.6%; P=0.017) and 4 (60.0% versus 19.6%; PConclusions This potential antiviral and/or immune-modulating activity of LMWH needs further in vivo confirmations by randomized controlled trials.

The landscape of central nervous system HIV infection is rapidly changing, leading to the recognition of a new constellation of overlapping syndromes and to a better insight for the elder ones. Among these, progressive multifocal leukoencephalopathy (PML) still poses several diagnostic and therapeutic challenges; nevertheless, recent developments in understanding PML in patients with multiple sclerosis may have benefitted HIV-positive patients suffering from PML too. We describe a peculiar case of PML-immune reconstitution inflammatory syndrome (IRIS) presenting a punctate pattern with "milky way" appearance on magnetic resonance imaging. Despite the fact that brain imaging and histopathology remain the mainstays for extricating through the expanding galaxy of HIV-related central nervous system dysimmune syndromes and although punctate pattern has been already well acknowledged as a suggestive finding of PML among patients on natalizumab, this radiological presentation is still poorly recognised in AIDS-related PML cases, leading to possible life-threatening diagnostic delays. This is also the first report about intravenous immunoglobulin treatment in AIDS-related PML-IRIS; the favourable clinical and radiological outcome of our case and the preliminary administrations of intravenous immunoglobulins in natalizumab-associated PML-IRIS from literature support probable benefits also among HIV-positive patients.

Objective HIV infection chronically affects the central nervous system (CNS). Olfactory mucosa is a unique site in the respiratory tract that is directly connected to the CNS; thus we wanted to evaluate olfactory mucosa as a surrogate of CNS sampling. Design We conducted a preliminary study examining HIV populations and susceptible cells in the olfactory mucosa. Methods Olfactory mucosa was sampled by minimally invasive brushing. Cerebrospinal fluid (CSF) analyses were performed as per routine clinical procedures. Olfactory marker protein, CD4+, CD8+, and trans-activator of transcription (TAT) expressions were assessed by immunohistochemistry. Plasma, CSF, and olfactory mucosa HIV-RNA were quantified using the Cobas AmpliPrep/Cobas TaqMan assay, whereas HIV proviral DNA was evaluated on peripheral blood mononuclear cell and olfactory mucosa. HIV-1 env deep sequencing was performed for phylogenetic analysis. Results Among ART-naive participants, 88.2% (15/17), and among ART-treated participants, 21.4% (6/28) had detectable HIV-RNA in samples from their olfactory mucosa; CSF escape was more common in patients with olfactory mucosa escape (50 vs. 7.9%; P = 0.010). Olfactory mucosa samples contained few cells positive for CD4, CD8, or HIV-DNA, and no HIV TAT-positive cells, indicating that this approach efficiently samples virions in the olfactory mucosa, but not HIV-infected cells. Yet, using a deep sequencing approach to phylogenetically compare partial HIV env genes in five untreated participants, we identified distinct viral lineages in the OM. Conclusions The results of this study suggest that nasal brushing is a well tolerated and useful technique for sampling the olfactory mucosa. HIV-RNA was detected in most naive and in some treated patients, warranting larger longitudinal studies.

Despite the substantial changes resulting from the introduction of combination antiretroviral therapy (cART), the prevalence of HIV-associated neurocognitive disorders (HAND) remains substantial. Blood–brain barrier impairment (BBBi) is a frequent feature in people living with HIV (PLWH) and it may persist despite effective antiretroviral treatment. A cross-sectional study was performed in PLWH who underwent lumbar puncture for clinical reasons or research protocols and several cerebrospinal fluid biomarkers were studied. BBBi was defined as cerebrospinal fluid-to-serum albumin ratio (CSAR) &gt, 6.5 (&lt, 40 years) or &gt, 8 (&gt, 40 years). We included 464 participants: 147 cART-naïve and 317 on cART. Male sex was prevalent in both groups (72.1% and 72.2% respectively), median age was 44 (38–52) years in naïve and 49 (43–57) years in treated subjects. BBBi was observed in 35.4% naïve and in 22.7% treated participants, the use of integrase inhibitors was associated with a lower prevalence (18.3 vs. 30.9%, p = 0.050). At multivariate binary logistic regression (including age and sex) nadir CD4 cell count (p = 0.034), presence of central nervous system (CNS) opportunistic infections (p = 0.024) and cerebrospinal fluid (CSF) HIV RNA (p = 0.002) in naïve participants and male sex (p = 0.021), a history of CNS opportunistic infections (p = 0.001) and CSF HIV RNA (p = 0.034) in treated patients were independently associated with BBBi. CSF cells and neopterin were significantly higher in participants with BBBi. BBBi was prevalent in naïve and treated PLWH and it was associated with CSF HIV RNA and neopterin. Systemic control of viral replication seems to be essential for BBB integrity while sex and treatment influence need further studies.

Recently, large-scale screening for COVID-19 has presented a major challenge, limiting timely countermeasures. Therefore, the application of suitable rapid serological tests could provide useful information, however, little evidence regarding their robustness is currently available. In this work, we evaluated and compared the analytical performance of a rapid lateral-flow test (LFA) and a fast semiquantitative fluorescent immunoassay (FIA) for anti-nucleocapsid (anti-NC) antibodies, with the reverse transcriptase real-time PCR assay as the reference. In 222 patients, LFA showed poor sensitivity (55.9%) within two weeks from PCR, while later testing was more reliable (sensitivity of 85.7% and specificity of 93.1%). Moreover, in a subset of 100 patients, FIA showed high sensitivity (89.1%) and specificity (94.1%) after two weeks from PCR. The coupled application for the screening of 183 patients showed satisfactory concordance (K = 0.858). In conclusion, rapid serological tests were largely not useful for early diagnosis, but they showed good performance in later stages of infection. These could be useful for back-tracing and/or to identify potentially immune subjects.

People living with HIV (PLWH) are aging and will receive life-long treatment: despite substantial improvement in drug efficacy and tolerability, side effects still occur and they can blunt antiretroviral treatment effectiveness. Since age may affect drug exposure and may be associated with side-effects we aimed at reviewing available data on the effect of age on antiretrovirals' pharmacokinetics in adult patients.We searched public databases and major conference proceedings for data on age and pharmacokinetics/pharmacodynamics in PLWH. We limited our review to currently used drugs and focused on population pharmacokinetics and physiologically-based pharmacokinetic modeling studies.Available evidence of a potential detrimental effect in elderly PLWH is limited by study design and small sample sizes. Careful consideration of undoubtful benefits and potential harms is advised when prescribing ARVs to geriatric patients and the knowledge of pharmacokinetics changes need to be included in the process. With the 'greying' of the pandemic we need studies with a specific focus on geriatric patients living with HIV that will consider specific phenotypes and associated changes (including sarcopenia).

Background The disease caused by the severe acute respiratory syndrome coronavirus 2 was named coronavirus disease 2019 and classified as a global public health emergency. The evidence related to the impact of coronavirus disease 2019 on pregnancy is limited to the second and third trimester of pregnancy, whereas data on the first trimester are scant. Many viral infections can be harmful to the fetus during the first trimester of pregnancy, and whether severe acute respiratory syndrome coronavirus 2 is one of them is still unknown. Objective With this study, we evaluated severe acute respiratory syndrome coronavirus 2 infection as a risk factor for early pregnancy loss in the first trimester of pregnancy. Furthermore, coronavirus disease 2019 course in the first trimester was assessed. Study Design Between February 22 and May 21, 2020, we conducted a case-control study at S. Anna Hospital, Turin, among pregnant women in their first trimester, paired for last menstruation. The cumulative incidence of coronavirus disease 2019 was compared between women with spontaneous abortion (case group, n=100) and those with ongoing pregnancy (control group, n=125). Current or past infection was determined by the detection of severe acute respiratory syndrome coronavirus 2 from nasopharyngeal swab and severe acute respiratory syndrome coronavirus 2 immunoglobulin G and immunoglobulin M antibodies in a blood sample. Patient demographics, coronavirus disease 2019–related symptoms, and the main risk factors for abortion were collected. Results Of 225 women, 23 (10.2%) had a positive test result for coronavirus disease 2019. There was no difference in the cumulative incidence of coronavirus disease 2019 between the cases (11/100, 11%) and the controls (12/125, 9.6%) (P=.73). Logistic regression analysis confirmed that coronavirus disease 2019 was not an independent predictor of early pregnancy loss (odds ratio, 1.28; confidence interval, 0.53–3.08). Coronavirus disease 2019–related symptoms in the first trimester were fever, anosmia, ageusia, cough, arthralgia, and diarrhea; no cases of pneumonia or hospital admission owing to coronavirus disease 2019–related symptoms were recorded. No difference in the incidence of symptoms was noted between the 2 groups. Conclusion Severe acute respiratory syndrome coronavirus 2 infection during the first trimester of pregnancy does not seem to predispose to early pregnancy loss; its cumulative incidence did not differ between women with spontaneous abortion and women with ongoing pregnancy. Coronavirus disease 2019 appears to have a favorable maternal course at the beginning of pregnancy, consistent with what has been observed during the second and third trimesters.

Therapeutic options to treat HIV infection have widened in the past years, improving both effectiveness and tolerability, but nucleoside reverse transcriptase inhibitors (NRTIs) are still considered the standard backbone of the combination regimens. Therapeutic drug monitoring (TDM) can be useful for these drugs, due to concentration–effect relationship, with risk of ineffectiveness, toxicity or adherence concerns: in this scenario, robust and multiplexed methods are needed for an effective TDM activity. In this work, the first validated ultra-high spectrometry liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) method is described for the high-sensitive simultaneous quantification of all the currently used NRTIs in human plasma, including tenofovir alafenamide (TAF), following FDA and EMA guidelines. The automated sample preparation consisted in the addition of an internal standard (IS) working solution, containing stable-isotope-linked drugs, protein precipitation and drying. Dry extracts were reconstituted with water, then, these underwent reversed phase chromatographic separation: compounds were detected through electrospray ionization and multiple reaction monitoring. Accuracy, precision, recovery and IS-normalized matrix effect fulfilled guidelines’ requirements. The application of this method on samples from people living with HIV (PLWH) showed satisfactory performance, being capable of quantifying the very low concentrations of tenofovir (TFV) in patients treated with TAF.

AIM People living with HIV (PLWH) have a high burden of comorbidities and concomitant medication use. The aim of this study was to analyse the prevalence, predictors and patterns of polypharmacy (PP) in a large therapeutic drug monitoring (TDM) registry. METHODS We searched our TDM registry and categorized co-medications into 26 drug classes. We included patients with at least one medication recorded: PP and severe polypharmacy (sPP) were defined as the concomitant use of ≥5 or ≥10 nonantiretroviral/nonantitubercular drugs. Multivariable binary logistic analysis were conducted for identifying PP/sPP predictors. A hierarchical average-linkage cluster analysis was performed among drug classes. RESULTS We included 2432 participants (1158 PLWH) aged 49.6 years (± 14.4) in the 2016-2020 period. A higher number of concomitant medications (4 vs 3.1, P

Background: Emerging evidence supports the “variolation hypothesis” in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), but the derivative idea that the viral load of index cases may predict disease severity in secondary cases could be unsubstantiated. We assessed whether the prevalence of symptomatic infections, hospitalization, and deaths in household contacts of 2019 novel coronavirus disease (COVID-19) cases differed according to the SARS-CoV-2 PCR cycle threshold (Ct) from nasal-pharyngeal swab at diagnosis of linked index cases.Methods: Cross-sectional study on household contacts of COVID-19 cases randomly sampled from all the infections diagnosed in March at our Microbiology Laboratory (Amedeo di Savoia, Turin). Data were retrospectively collected by phone interviews and from the Piedmont regional platform for COVID-19 emergency. Index cases were classified as high (HVl) and low viral load (LVl) according to two exploratory cut-offs of RdRp gene Ct value. Secondary cases were defined as swab confirmed or symptom based likely when not tested but presenting compatible clinical picture.Results: One hundred thirty-two index cases of whom 87.9% symptomatic and 289 household contacts were included. The latter were male and Caucasian in 44.3 and 95.8% of cases, with a median age of 34 years (19–57). Seventy-four were swab confirmed and other 28 were symptom based likely secondary cases. Considering both, the contacts of HVl and LVl did not differ in the prevalence of symptomatic infections nor COVID-19-related hospitalization and death. No difference in median Ct of index cases between symptomatic and asymptomatic, hospitalized and not hospitalized, or deceased and survived secondary cases was found. Negative findings were confirmed after adjusting for differences in time between COVID-19 onset and swab collection of index cases (median 5 days) and after removing pediatric secondary cases.Conclusions: The amount of SARS-CoV-2 of the source at diagnosis does not predict clinical outcomes of linked secondary cases. Considering the impelling release of assays for SARS-CoV-2 RNA exact quantification, these negative findings should inform clinical and public health strategies on how to interpret and use the data.

We report herein the longest-lasting study of SARS-CoV-2 antibody profile in pregnancy, from first trimester-infection to delivery. Seventeen out of 164 pregnant women tested positive for COVID-19. Throughout pregnancy, the neutralizing antibody titer remained stable, whilst a significant decline in the non-neutralizing antibodies was observed after 16 weeks of gestation. All the newborns of women who developed IgG antibodies showed the presence of the same antibodies in arterial cord blood. Knowledge on the longevity and type of SARS-CoV-2 antibody response may help to guide vaccination strategies in pregnancy.

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 (pvalues > 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 (rho = 0.374,p = 0.016) and age (rho = 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.

This Italian observational real-world study aims to assess in chronic hepatitis C virus (HCV) patients treated with pangenotypic direct acting agents (pDAAs) glecaprevir/pibrentasvir (GLE/PIB) or sofosbuvir/velpatasvir (SOF/VEL) the potential drug–drug interactions (DDIs) with concomitant medications prescribed, with a focus on cardiovascular and system nervous (CNS) co-medications. Data were collected from administrative databases covering 6.9 million health-assisted individuals. All patients prescribed SOF/VEL or GLE/PIB between 11/2017 and 12/2018 were included. Patients were analyzed while on DAA. DDIs were identified according to the Liverpool University tool. Overall, 3,181 HCV patients were included: 1619 in the GLE/PIB cohort and 1,562 in the SOF/VEL cohort. SOF/VEL patients were generally older than GLE/PIB ones (mean age 58.4 vs. 53.1, p &lt, 0.001) and had more cardiovascular and CNS comorbidities (58% vs. 42%, p &lt, 0.001 and 33% vs. 28%, p = 0.002, respectively). Contraindications due to DDIs in the GLE/PIB cohort affected 9.3% and 3.2% of patients before and on DAA, respectively, while the percentages in the SOF/VEL cohort were 3.2% before and 0.4% after pDAAs initiation. Among GLE/PIB patients, 2.7% had cardiovascular drugs (all statins) contraindicated while on DAA. The potential DDIs between cardiovascular drugs and SOF/VEL were mainly with statins (5%). SOF/VEL was prescribed in patients with older age and with more cardiovascular and CNS comorbidities. Despite this, a proportion of contraindicated drugs lower than that of GLE/PIB was registered.

Background Low-level HIV viremia originating from virus reactivation in HIV reservoirs is often present in cART treated individuals and represents a persisting source of immune stimulation associated with sub-optimal recovery of CD4+ T cells. The HIV-1 Tat protein is released in the extracellular milieu and activates immune cells and latent HIV, leading to virus production and release. However, the relation of anti-Tat immunity with residual viremia, persistent immune activation and CD4+ T-cell dynamics has not yet been defined. Methods Volunteers enrolled in a 3-year longitudinal observational study were stratified by residual viremia, Tat serostatus and frequency of anti-Tat cellular immune responses. The impact of anti-Tat immunity on low-level viremia, persistent immune activation and CD4+ T-cell recovery was investigated by test for partitions, longitudinal regression analysis for repeated measures and generalized estimating equations. Findings Anti-Tat immunity is significantly associated with higher nadir CD4+ T-cell numbers, control of low-level viremia and long-lasting CD4+ T-cell recovery, but not with decreased immune activation. In adjusted analysis, the extent of CD4+ T-cell restoration reflects the interplay among Tat immunity, residual viremia and immunological determinants including CD8+ T cells and B cells. Anti-Env immunity was not related to CD4+ T-cell recovery. Interpretation Therapeutic approaches aiming at reinforcing anti-Tat immunity should be investigated to improve immune reconstitution in people living with HIV on long-term cART. Trial registration ISS OBS T-002 ClinicalTrials.gov identifier: NCT01024556 Funding Italian Ministry of Health, special project on the Development of a vaccine against HIV based on the Tat protein and Ricerca Corrente 2019/2020.

Background The spread of severe acute respiratory coronavirus 2 (SARS-CoV-2) among active workers is poor known. The aim of our study was to evaluate the seroprevalence of immunoglobulin G (IgG) among a convenience sample of workers and to identify high-risk job sectors during the first pandemic way. Methods We conducted a cross-sectional study among workers tested for SARS-CoV-2 between 28 March and 7 August 2020, recorded by a private healthcare center located in North-West Italy. Association among seroprevalence and demographic and occupational variables was evaluated using chi square test and the seroprevalence and 95% confidence intervals (CI) were calculated. Results We collected the results for 23568 serological tests from a sample of 22708 workers from about 1000 companies. Median age was 45 years and about 60% of subjects were male. The overall seroprevalence was 4.97% [95%CI 4.69–5.25]. No statistical difference was found among gender while seroprevalence was associated with subjects’ age, geographical location, and occupational sector. Significantly higher values of positivity were observed for the logistics sector (31.3%), weaving factory (12.6%), nursing homes (9.8%), and chemical industry (6.9%) workers. However, we observed some clusters of cases in single companies independently from the sector. Then, a detailed focus on 940 food workers shown a seroprevalence of 5.21% [95%CI 3.79–6.63] and subjects who self-reported COVID-19 symptoms and who worked during lockdown had a higher probability of being infected (p < 0.001). Conclusions Data obtained might be useful for future public health decision; more than occupation sector, it seems that failure on prevention system in single companies increase the SARS-CoV-2 transmission.

Hepatitis B virus (HBV) infection is a global health problem with different immunological phases and therapeutic approaches. The serological condition of inactive carrier (IC) was recently well defined as a clinical and virological stable status, in which specific treatment is usually deferred, while the active chronic hepatitis B (CHB) condition requires an immediate treatment strategy. Recently, a possible broad antiviral effect of oxysterols, in particular 25-hydroxycholesterol (25OHC) and 27-hydroxycholesterol (27OHC), was observed, as most likely linked to the positive modulation of innate immunity, but no clear evidence is available about their possible role in chronic HBV infection. Thus, we examined the relationship between the plasma levels of oxysterols and the disease condition of 40 HBV patients, without treatment at the start of the study. Of these, 33 were ICs and 7 were active CHB subjects. A marked reduction of 25OHC and 27OHC plasma levels was detectable in all active CHB recruited patients, while the plasma values observed in ICs all remained within the physiological range. No difference was observed between the two groups of patients with regard to the plasma levels of 24-hydroxycholesterol (24OHC). Further, the plasma level of 27OHC ≥ 140 μg/L was shown to be predictive of an inactive carrier status. This cohort study points to 27OHC as a good candidate biomarker to differentiate active and inactive CHB status. An increasing bulk of research reports is supporting the very likely contribution of this oxysterol to the immunological control of chronic hepatitis B.

ObjectiveGiven the aging of people living with HIV (PLWH) and the high prevalence of HIV-associated neurocognitive disorders, we aimed at describing the clinical, instrumental, and CSF features of PLWH diagnosed with Alzheimer dementia (AD).MethodsThe databases of 3 large Italian outpatient clinics taking care of more than 9,000 PLWH were searched for the diagnosis of AD. After obtaining patients' or their next of kin's consent for publication, anonymous data were collected in an excel spreadsheet and described. Routinely collected CSF biomarkers and radiologic imaging results were recorded whether available.ResultsFour patients were included in this case series who were diagnosed with AD aged between 60 and 74 years. All participants were on highly active antiretroviral therapy and showed nondetectable serum HIV RNA. Memory impairment was the most prominent cognitive feature. The diagnosis was obtained considering the exclusion of other potential causes, MRI and fluorodeoxyglucose-PET features, and, in (in 2/4), CSF AD biomarkers levels. In 1 patient, longitudinal CSF tau/p-tau increased, and beta-amyloid1–42 decreased over time despite antiretroviral therapy containing nucleotide reverse transcriptase inhibitors.ConclusionsIn older PLWH cognitive symptoms may represent the onset of AD: a multidisciplinary team may be needed for reaching a likely in vivo diagnosis.

To date, there is no severe acute respiratory syndrome coronavirus 2- (SARS-CoV-2)-specific prognostic biomarker available. We assessed whether SARS-CoV-2 cycle threshold (Ct) value at diagnosis could predict novel CoronaVirus Disease 2019 (COVID-19) severity, clinical manifestations, and six-month sequelae. Hospitalized and outpatient cases were randomly sampled from the diagnoses of March 2020 and data collected at 6 months by interview and from the regional database for COVID-19 emergency. Patients were stratified according to their RNA-dependent-RNA-polymerase Ct in the nasopharyngeal swab at diagnosis as follows: Group A ≤20.0, 20.0&lt, group B ≤28.0, and Group C &gt, 28.0. Disease severity was classified according to a composite scale evaluating hospital admission, worst oxygen support required, and survival. Two hundred patients were included, 27.5% in Groups A and B both, 45.0% in Group C, 90% of patients were symptomatic and 63.7% were hospitalized. The median time from COVID-19 onset to swab collection was five days. Lethality, disease severity, type, and number of signs and symptoms, as well as six-month sequelae distributed inversely among the groups with respect to SARS-CoV-2 Ct. After controlling for confounding, SARS-CoV-2 Ct at diagnosis was still associated with COVID-19-related death (p = 0.023), disease severity (p = 0.023), number of signs and symptoms (p &lt, 0.01), and presence of six-month sequelae (p &lt, 0.01). Early quantification of SARS-CoV-2 may be a useful predictive marker to inform differential strategies of clinical management and resource allocation.

Four pre-exposure prophylaxis (PrEP) users with gastrointestinal disorders (sleeve gastrectomy, terminal ileitis, celiac disease, or chronic diarrhea) and receiving oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) were included. Despite self-reported high adherence, trough plasma tenofovir concentrations (after supervised intake) were significantly lower in these patients than in PrEP recipients without gastrointestinal disorders (21 ± 9.1 versus 138 ± 85 ng/ml). PrEP users with gastrointestinal disorders may need increased TDF doses or alternative prophylactic measures.

Evidence for the real impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on preterm birth is unclear, as available series report composite pregnancy outcomes and/or do not stratify patients according to disease severity. The purpose of the research was to determine the real impact of asymptomatic/mild SARS-CoV-2 infection on preterm birth not due to maternal respiratory failure. This case-control study involved women admitted to Sant Anna Hospital, Turin, for delivery between 20 September 2020 and 9 January 2021. The cumulative incidence of Coronavirus disease-19 was compared between preterm birth (case group, n = 102) and full-term delivery (control group, n = 127). Only women with spontaneous or medically-indicated preterm birth because of placental vascular malperfusion (pregnancy-related hypertension and its complications) were included. Current or past SARS-CoV-2 infection was determined by nasopharyngeal swab testing and detection of IgM/IgG antibodies in blood samples. A significant difference in the cumulative incidence of Coronavirus disease-19 between the case (21/102, 20.5%) and the control group (32/127, 25.1%) (P= 0.50) was not observed, although the case group was burdened by a higher prevalence of three known risk factors (body mass index > 24.9, asthma, chronic hypertension) for severe Coronavirus disease-19. Logistic regression analysis showed that asymptomatic/mild SARS-CoV-2 infection was not an independent predictor of spontaneous and medically-indicated preterm birth due to pregnancy-related hypertension and its complications (0.77; 95% confidence interval, 0.41-1.43). Pregnant patients without comorbidities need to be reassured that asymptomatic/mild SARS-CoV-2 infection does not increase the risk of preterm delivery. Preterm birth and severe Coronavirus disease-19 share common risk factors (i.e., body mass index > 24.9, asthma, chronic hypertension), which may explain the high rate of indicated preterm birth due to maternal conditions reported in the literature.

Scope Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has become pandemic, reaching almost one million death worldwide. At present standard treatment for coronavirus disease 2019 (COVID-19) is not well defined because the evidence, either from randomized or observational studies, with conflicting results, has led to rapid changes in treatment guidelines. Our aim was to narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and interpretation of the data by experts who are treating patients in the frontline setting. Methods The panel conducted a detailed review of the literature and eventual press releases from randomized clinical trials for each possible available treatment. Inductive PubMed search waws performed for publications relevant to the topic, including all clinical trials conducted. The result was a flowchart with treatment indications for patients with COVID-19. Implications After 6 months of a pandemic situation and before a possible second coronavirus wave descends on Europe, it is important to evaluate which drugs proved to be effective while also considering that results from many randomized clinical trials are still awaited. Indeed, among treatments for COVID-19, only glucocorticoids have resulted in an association with a significant decrease in mortality in published randomized controlled trials. New therapeutic strategies are urgently needed.

Purpose: To describe a strategy to reduce Covid-19 spread among healthcare workers and provide ophthalmologists with recommendations useful for a possible second wave of Covid-19 in Autumn. Methods: Epidemiological surveillance at the Cà Foncello Hospital (Veneto, Italy) since 24 February 2020 to 24 April 2020 when the municipality of Treviso was hit by the Covid-19 outbreak. The number of naso-pharigeal (NP) swabs performed was 7010. Results: The number of infected among healthcare workers was 209/ 3924 (5.32%): medical doctors: 28 cases / 498 (5.6%). None among ophthalmologists; specialized nurses: 86/1294 (6.4%) None in the ophthalmic unit; intermediate care technicians: 68/463 (14.7%). The 46% of the positive tested were asymptomatic. We share key suggested actions for the reorganization in ophthalmological services: be part of a global epidemiological local strategy of containment (Testing, Tracing, Treating); protect your department: Keep on screening patients by telephone interview before entering the hospital; promote continuous and appropriate use of PPE both for doctors and for patients; make any effort to obtain a continuous flow of patients in every line of the ophthalmic service; treat appropriately any single patient with vision threatening condition; avoid unnecessary or futile testings and examinations. Conclusion: The Treviso model shows that it is possible and safe to keep on performing high risk hospital activities like ophthalmology, even in the epicenter of covid outbreak, if adequate actions are performed. We discuss about the value of NP swabs and serological tests as a strategy in case of a second wave of infections.

Introduction Tubercolous meningitis (TBM) is an important disease leading to morbidity, disability and mortality that primarily affects children and immune-depressed patients. Specific neuromarkers predicting outcomes, severity and inflammatory response are still lacking. In recent years an increasing number of evidences show a possible role for infective agents in developing neurodegenerative diseases. Methods We retrospectively included 13 HIV-negative patients presenting with meningeal tuberculosis. Lumbar punctures were performed for clinical reasons and CSF biomarkers were routinely available: we analyzed blood brain barrier permeability (CSF to serum albumin ratio, “CSAR”), intrathecal IgG synthesis, (CSF to serum IgG ratio), inflammation (neopterin), amyloid deposition (1-42 β-amyloid), neuronal damage (T-tau, P-tau, 14.3.3) and astrocytosis (S-100 β). Results Patients were 83% male and 67 % Caucasian with a median age of 51 years(24.5-63.5 IQR). Apart from altered CSAR (median value 18.4, 17.1-30.9 IQR), neopterin (14.3 ng/ml, 9.7-18.8) and IgG ratios (15.4, 7.9-24.9) patients showed very low levels of 1-42 β-amyloid in their CSF (348.5 pg/mL,125-532.2). Protein 14.3.3. tested altered in 38.5% cases. T-tau, ptau and S100Beta were in the range of normality. Altered low level of beta amyloid correlated over time with classical TBm findings and altered neuromarkers.Conclusion CSF Biomarkers from patients with TBM were compatible with inflammation, blood brain barrier damage and impairment in beta amyloid metabolism. Aβ1-42 could be tested as a prognostic markers, backing the routine use of available neuromarkers. To our knowledge this is the first case showing such low levels of Aβ1-42 in TBM; its accumulation, drove by neuroinflammation related to infections, can be central in understanding neurodegenerative diseases.

Recently, anti-HIV treatment has achieved high efficacy and tolerability. Nevertheless, few data are available about the intracellular penetration of antiretrovirals, partly due to the technical challenges related to intracellular quantification. This work aimed to validate an ultra-high performance liquid chromatography (UHPLC) tandem mass spectrometry (MS/MS) method for the simultaneous quantification of maraviroc, nevirapine, rilpivirine, dolutegravir, raltegravir, cobicistat, darunavir, ritonavir, atazanavir, efavirenz, elvitegravir, and etravirine within peripheral blood mononuclear cells (PBMCs) and apply it to samples from patients. PBMCs were isolated by density gradient on cell preparation tubes (CPT). Samples were prepared by addition of internal standards (IS), sonication, centrifugation, and drying. Reconstituted extracts underwent chromatographic separation by reversed phase UHPLC and detection was performed by electrospray ionization and multiple reaction monitoring. Method validation followed FDA and EMA guidelines, showing acceptable accuracy, precision, recovery and IS-normalized matrix effect. The application to 56 samples from patients undergoing antiretroviral treatment provided description of intracellular penetration, showing method eligibility for future studies.

Background The treatment of drug-sensitive tuberculosis (TB) is highly effective; however, many patients have suboptimal drug exposure, which possibly explains treatment failures and selection of resistance. This study aimed to describe the prevalence and determinants of suboptimal maximal concentrations (Cmax) for anti-TB drugs. Methods An observational study was conducted in patients receiving first-line anti-TB treatment. At two early time points (T1 and T2), blood samples were withdrawn 2 hours post-dose (Cmax) and drug concentrations were measured. Data were expressed as medians (interquartile ranges). Results The study included 199 participants: 72.9% were male and the median age was 39.8 years (27.5–51.4). The median Cmax at T1 and T2 were 7950 ng/mL and 7122 ng/mL (rifampicin), 3260 ng/mL and 3185 ng/mL (isoniazid), 4210 ng/mL and 5742 ng/mL (ethambutol), and 31 008 ng/mL and 30 352 ng/mL (pyrazinamide), respectively. Higher doses/kg and other variables (being born in Italy and female gender for rifampicin, older age and proton pump inhibitor use for isoniazid, female gender and older age for pyrazinamide) were identified by multivariate linear regression analysis. Participants with a higher body mass index received lower doses/kg of all anti-TB drugs. Suboptimal Cmax at T1 and T2 were observed in 60% and 66% (rifampicin), 54% and 55% (isoniazid), 33% and 39% (ethambutol), 20% and 11% (pyrazinamide) of patients. Despite 21% of patients at T1 and 24% at T2 showing two or more drugs with suboptimal exposure, no effect on treatment outcome was observed. Discussion The majority of patients receiving first-line anti-TB drugs had low isoniazid and rifampin Cmax. Increased doses or the use of therapeutic drug monitoring in selected patients may be advised.

OBJECTIVE Aim of this study was to compare cerebrospinal fluid (CSF) virological control, biomarkers and neurocognition of neurologically symptomatic patients on dual antiretroviral therapies (dual therapy) vs. 2 nucleoside reverse transcriptase inhibitors-based three-drug regimens (triple therapy). DESIGN Retrospective monocentric cross-sectional study. METHODS We analysed data from people living with HIV undergoing lumbar puncture for clinical/research reasons with plasma HIV-RNA less than 200 copies/ml and neurological/neurocognitive symptoms without significant contributing comorbidities. We measured CSF HIV-RNA, inflammation, blood-brain barrier integrity, neuronal damage and astrocytosis biomarkers (five biomarkers by ELISA and five indices by immunoturbidimetry) and recorded the neurocognitive performance (14 tests). CSF escape was defined as any case of CSF HIV-RNA 0.5 Log10 higher than viraemia or any case of detectable CSF HIV-RNA coupled with undetectable viraemia. RESULTS A total of 78 patients on triple therapy and 19 on dual therapy were included. Overall, 75.3% male, median age 51 years (46-58), current CD4 count 545 cells/μl (349-735), time on current regimens 18 months (8-29), but length of plasma suppression 32 months (14-94). The two groups did not differ in terms of HIV-associated neurological diagnoses, demographic and viro-immunological features. Undetectable CSF HIV-RNA (73.7% in dual therapy vs. 78.2% in triple therapy, p.67) and CSF escape (21.1% in dual therapy vs. 19.2% in triple therapy, p.86) did not differ. No difference was observed in depression, anxiety, neurocognition (in 63 participants) nor in any tested biomarker. CONCLUSION In people living with HIV with neurological/neurocognitive symptoms, peripherally effective dual therapy can show CSF virosuppression, inflammation, neuronal and astrocyte integrity and neurocognition comparable to triple therapy.

The development of therapeutic agents against SARS-CoV-2/COVID-19 faces numerous barriers and a multidisciplinary approach to evaluating drug efficacy and toxicity is essential. Experimental and preclinical data should be integrated into a comprehensive analysis, where drug potency, the timing of therapy initiation, drug combinations, variability in systemic and local drug exposure and short- and long-term toxicities represent fundamental factors for the rational identification of candidates and prioritization of clinical investigations. Although the identification of SARS-CoV-2 therapeutics is a priority, rigorous and transparent methodologies are crucial to ensure that accelerated research programmes result in high-quality and reproducible findings.

BackgroundEvidence for the impact of COVID-19 during the second and the third trimester of pregnancy is limited to a relatively small series, while data on the first trimester are scant. With this study we evaluated COVID-19 infection as a risk factor for spontaneous abortion in first trimester of pregnancy.MethodsBetween February 22 and May 21, 2020, we conducted a case-control study at S. Anna Hospital, Turin, among first trimester pregnant women, paired for last menstruation. The cumulative incidence of COVID-19 was compared between women with spontaneous abortion (case group, n=100) and those with ongoing pregnancy (control group, n=125). Current or past infection was determined by detection of SARS-CoV-2 from nasopharingeal swab and SARS- CoV-2 IgG/IgM antibodies in blood sample. Patient demographics, COVID-19-related symptoms, and the main risk factors for abortion were collected.FindingsTwenty-three (10.2%) of the 225 women tested positive for COVID-19 infection. There was no difference in the cumulative incidence of COVID-19 between the cases (11/100, 11%) and the controls (12/125, 9.6%) (p=0.73). Logistic regression analysis confirmed that COVID-19 was not an independent predictor of abortion (1.28 confidence interval 0.53-3.08).InterpretationCOVID-19 infection during the first trimester of pregnancy does not appear to predispose to abortion; its cumulative incidence did not differ from that of women with ongoing pregnancy.

OBJECTIVE The current study aimed to investigate whether cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) or cytomegalovirus (CMV) DNA was associated with viral, inflammatory and neuronal damage biomarkers in people living with HIV (PLWH). DESIGN A cross-sectional diagnostic study on CSF fluid samples in patients undergoing lumbar punctures for clinical reasons, to better understand the role of EBV and CMV in the CNS on HIV RNA replication, blood-brain-barrier (BBB) damage and biomarkers of neuronal damage/inflammation. METHODS EBV, CMV DNA and HIV RNA were measured on CSF, through real time (RT)-PCR, from PLWHs undergoing lumbar punctures for clinical reasons (excluding oncho-haematological comorbidities). Immune-enzymatic assays evaluated blood-brain barrier inflammation and damage. Patients were stratified according to plasma HIV RNA levels in viremic (≥50 copies/ml) and aviremic (

BackgroundData on bone health and renal impairment in people with human immunodeficiency virus (HIV) in resource-limited settings are limited. The primary aim of this study was to investigate the potential role of calcaneal quantitative ultrasonography (QUS) in predicting bone mineral density (BMD) reduction in a population of Ugandan HIV-infected individuals receiving long-term antiretroviral therapy; the secondary end point was to assess the prevalence of proximal tubular dysfunction and the correlation between elevated urinary retinol-binding protein–urinary creatinine ratio (uRBP/uCr) and reduced BMD.MethodsWe conducted a cross-sectional study at the Infectious Diseases Institute, Kampala, Uganda. We included 101 HIV-infected adults who had been receiving continuous antiretroviral therapy for ≥10 years and had undergone dual-energy x-ray absorptiometry (DXA) during the previous 12 months. All patients underwent calcaneal QUS evaluation and urine sample collection.ResultsDXA BMD measurements were significantly associated (P ConclusionsCalcaneal QUS results showed a moderate correlation with DXA outputs. The identified high prevalence of subclinical tubular impairment also highlights the importance of expanding access to tenofovir disoproxil fumarate–sparing regimens in resource-limited settings.

Objectives Infections caused by multidrug-resistant Gram-negative bacteria are associated with high mortality. A relevant concern is the efficacy of antibiotic therapy in burn patients in whom pathophysiological changes strongly influence pharmacokinetic (PK) parameters. This study aimed to describe the PK parameters of meropenem in a population of burn patients. Methods Blood samples were collected immediately before and 2 h and 5 h after the start of intravenous drug administration. Plasma meropenem concentrations were determined using an ultra-performance liquid chromatography–photodiode array method. Results Seventeen burn patients were enrolled in the study. Thirteen patients (76%) were treated with meropenem for infections byPseudomonas aeruginosa or Acinetobacter baumannii isolated from blood or wounds. Mean Cmax, Cmin, AUC0–24, half-life, drug clearance and volume of distribution were 28.9 mg/L, 3.7 mg/L, 280.2 mg h/L, 2.0 h, 19.0 L/h and 44.4 L, respectively. Six patients (35%) achieved a Cmin ≥3.3 mg/L and seven patients (41%) achieved a Cmax ≥ 28.4 mg/L, whilst nine patients (53%) achieved an AUC0–24 of >226 mg h/L. Given a minimum inhibitory concentration (MIC) of 0.5 mg/L, all patients satisfied the target AUC/MIC of >125, but when the MIC rises to 2 mg/L (the ECOFF), only five patients reached the desired AUC/MIC. Regarding fT>MIC at an MIC of 2 mg/L with a 2-h infusion time, 13 patients (76%) achieved the PK target (>75%). Conclusion These data suggest that a combined 2-h infusion with a higher dosage of meropenem, including a loading dose, may be successful to achieve effective PK parameters.

The risk of vertical transmission during vaginal delivery in COVID-19 pregnant patient is currently a topic of debate. This case demonstrates that the neonatal contamination with SARS-CoV-2 during vaginal birth is possible, because of the presence of the virus in the rectum and feces of COVID-19 pregnant patients.

White matter hyperintensities (WMHs) have been associated with neurological complications including cognitive impairment. WMHs have been often described in HIV positive subjects and they have been linked to neurocognitive impairment, cerebrospinal fluid (CSF) residual viral replication and biomarkers of monocyte activation. Aim of this study was to grade WMHs in HIV-positive individuals using a simple visual scale and to explore their severity with clinical, neurocognitive and biomarker characteristics. Brain MRIs were retrospectively evaluated by two reviewers who rated WMHs following the "age-related white matter changes (ARWMC)" scale. 107 adult HIV-positive patients receiving lumbar punctures for clinical reasons were included. 70 patients (66.6%) were diagnosed with WMHs. Average WMH scores were higher in treated [7 (1-11)] vs. naïve individuals [3 (0-6)] (p = 0.008). Higher WHMs scores were observed in patients with chronic renal impairment along with chronic hepatitis (naïve) and longer HIV duration (treated participants). No consistent associations between plasma, CSF biomarkers and WMHs scores were found. 45 patients underwent full neurocognitive tests and WMHs scores were non-significantly higher in patients diagnosed with HAND [6.5 (0.5-8.3) vs. 1.5 (0-7), p = 0.165]; screening (IHDS and FAB), visuo-spatial (Corsi's) and auditory-verbal memory (disillabic words repetition) tests scored worse in patients with higher WMHs. In our population of HIV-positive patients with low CD4 nadir and partial CD4 cell recovery the burden of WMHs was associated with the duration of HIV infection and with commonly observed comorbidities (such as renal and hepatic impairment). Given the association with worse neurocognition, further studies on tailored interventions are needed.