Association between SARS-CoV-2 RNAemia, skewed T cell responses, inflammation, and severity in hospitalized COVID-19 people living with HIV.

Severe COVID-19 outcomes have been reported in people living with HIV (PLWH), yet the underlying pathogenetic factors are largely unknown. We therefore aimed to assess SARS-CoV-2 RNAemia and plasma cytokines in PLWH hospitalized for COVID-19 pneumonia, exploring associations with magnitude and functionality of SARS-CoV-2-specific immune responses. Eighteen unvaccinated PLWH (16/18 on cART; median CD4 T cell count 361.5/µL; HIV-RNA<50 cp/mL in 15/18) and 18 age/sex-matched people without HIV were consecutively recruited at a median time of 10 days from symptoms onset. PLWH showed greater SARS-CoV-2 RNAemia, a distinct plasma cytokine profile, and worse respiratory function (lower PaO2/FiO2nadir), all correlating with skewed T cell responses (higher perforin production by cytotoxic T cells as well as fewer and less polyfunctional SARS-CoV-2-specific T cells), despite preserved humoral immunity. In conclusion, these data suggest a link between HIV-related T cell dysfunction and poor control over SARS-CoV-2 replication/dissemination that may in turn influence COVID-19 severity in PLWH.

Genomic epidemiology of the main SARS-CoV-2 variants in Italy between summer 2020 and winter 2021.

Since the beginning of the pandemic, SARS-CoV-2 has shown a great genomic variability, resulting in the continuous emergence of new variants that has made their global monitoring and study a priority. This work aimed to study the genomic heterogeneity, the temporal origin, the rate of viral evolution and the population dynamics of the main circulating variants (20E.EU1, Alpha and Delta) in Italy, in August 2020-January 2022 period. For phylogenetic analyses, three datasets were set up, each for a different main lineage/variant circulating in Italy in that time including other Italian and International sequences of the same lineage/variant, available in GISAID sampled in the same times. The international dataset showed 26 (23% Italians, 23% singleton, 54% mixed), 40 (60% mixed, 37.5% Italians, 1 singleton) and 42 (85.7% mixed, 9.5% singleton, 4.8% Italians) clusters with at least one Italian sequence, in 20E.EU1  clade, Alpha and Delta variants, respectively. The estimation of tMRCAs in the Italian clusters (including >70% of genomes from Italy) showed that in all the lineage/variant, the earliest clusters were the largest in size and the most persistent in time and frequently mixed. Isolates from the major Italian Islands tended to segregate in clusters more frequently than those from other part of Italy. The study of infection dynamics showed a positive correlation between the trend in the effective number of infections estimated by BSP model and the Re curves estimated by birth-death skyline plot. The present work highlighted different evolutionary dynamics of studied lineages with high concordance between epidemiological parameters estimation and phylodynamic trends suggesting that the mechanism of replacement of the SARS-CoV-2 variants must be related to a complex of factors involving the transmissibility, as well as the implementation of control measures, and the level of cross-immunization within the population.

Efficacy of Dolutegravir versus Darunavir in Antiretroviral First-Line Regimens According to Resistance Mutations and Viral Subtype.

BACKGROUND: Dolutegravir (DTG)-based first-line regimens have shown superior efficacy versus darunavir (DRV)-based ones in randomized trials. We compared these two strategies in clinical practice, particularly considering the role of pre-treatment drug resistance mutations (DRMs) and of the HIV-1 subtype. MATERIALS AND METHODS: The multicenter Antiretroviral Resistance Cohort Analysis (ARCA) database was queried to identify HIV-1-positive patients starting a first-line therapy with 2NRTIs plus either DTG or DRV between 2013 and 2019. Only adult (≥18 years) patients with a genotypic resistance test (GRT) prior to therapy and with HIV-1 RNA ≥1000 copies/mL were selected. Through multivariable Cox regressions, we compared DTG- versus DRV-based regimens in the time to virological failure (VF) stratifying for pre-treatment DRMs and the viral subtype. RESULTS: A total of 649 patients was enrolled, with 359 (55.3%) and 290 (44.7) starting DRV and DTG, respectively. In 11 months of median follow-up time, there were 41 VFs (8.4 in 100 patient-years follow-up, PYFU) and 15 VFs (5.3 per 100 PYFU) in the DRV and DTG groups, respectively. Compared with a fully active DTG-based regimen, the risk of VF was higher with DRV (aHR 2.33; p = 0.016), and with DTG-based regimens with pre-treatment DRMs to the backbone (aHR 17.27; p = 0.001), after adjusting for age, gender, baseline CD4 count and HIV-RNA, concurrent AIDS-defining event and months since HIV diagnosis. Compared with patients harboring a B viral subtype and treated with a DTG-based regimen, patients on DRV had an increased risk of VF, both in subtype B (aHR 3.35; p = 0.011), C (aHR 8.10; p = 0.005), CRF02-AG (aHR 5.59; p = 0.006) and G (aHR 13.90; p < 0.001); DTG also demonstrated a reduced efficacy in subtypes C (versus B, aHR 10.24; p = 0.035) and CRF01-AE (versus B; aHR 10.65; p = 0.035). Higher baseline HIV-RNA and a longer time since HIV diagnosis also predicted VF. CONCLUSIONS: In line with randomized trials, DTG-based first-line regimens showed an overall superior efficacy compared with DRV-based regimens. GRT may still play a role in identifying patients more at risk of VF and in guiding the choice of an antiretroviral backbone.

SARS-CoV-2 infection clinical picture and outcomes in adults living with HIV: a cohort analysis.

Existing evidence about HIV and SARS-CoV-2 co-infection has, so far, yield conflicting results. Methods: This is a cohort, single center, clinical study aimed at identifying possible characteristics of PLWH that could correlate with the risk of acquiring SARS-CoV-2 and would influence the outcome. 155 cases of SARS-CoV-2 infection were compared with 307 PLWH who tested negative. No variable was associated with an increased risk of infection. SARS-CoV-2 PLWH were completely asymptomatic in 20.6% of cases. Factors associated with severe COVID-19 were age (P=0.001), diabetes (P=0.009) hypertension (P=0.004), cardiovascular disease (P=0.001) or an increasing number of chronic co-morbidities (P=0.002); only the first two variables retained statistical significance in a multivariable model. Only older age and a lower CD4 count were statistically associated with death in the multivariate model. Sixteen PLWH not included in the analysis were infected by SARS-Cov-2 after vaccination. In 4 cases the infection was completely asymptomatic, while in the remaining 12 cases the infection was mild and resembled a flu-like syndrome. Conclusions: No baseline characteristic defines patients at greater risk of SARS-CoV-2 infection. Older age and the presence of multi-comorbidities are risk factors for a severe clinical course. Lower CD4 counts correlate with a fatal outcome.

Long-term outcome of lamivudine/dolutegravir dual therapy in HIV-infected, virologically suppressed patients.

BACKGROUND: The use of DTG-containing two-drug regimens is one of the most promising solutions to the need to ease the management of HIV treatment without harming its efficacy and safety. We report long- term results in patients switched, while virologically suppressed, to the combination of dolutegravir (DTG) plus lamivudine (3TC). METHODS: This is a prospective, clinical, uncontrolled cohort enrolling ART-experienced people living with HIV (PLWH) with HIV-RNA < 50 copies/ml for 6 months or longer, negative hepatitis B virus surface antigen, and without known M184V/I mutations. Kaplan-Meiers curves are used to describe persistency of virological suppression on therapy and a Cox regression model to evaluate baseline characteristics and the risk of stopping therapy. RESULTS: 218 individuals switched their regimen since 2015. The mean estimated follow-up was of 64.3 months (95% CI 61.3-67.3) for approximately 1000 patient/years. After 5 years of follow-up, 77.1% were still on the DTG-3TC combination. No virologic failure was detected throughout the whole study period, and only 15 subjects presented single isolated viral blips above 50 copies/ml. Most patients stopped therapy because of reasons unrelated to study drugs (lost to follow-up; patients' decision; moved to other Centers), but due to the unselected nature of the casuistry; 11 subjects died in the 5 years of follow-up mostly because of pre-existing co-morbidities (6 neoplastic diseases and 2 end-stage liver disease). The median baseline CD4 count was 669 cells/mcl (IQR 483-927). After 5 years it raised to 899 cells/mcl (IQR 646-1160) (P < 0.001) without a significant change of CD8 counts that lowered from 767 cells/mcl (IQR 532-1034) to 683 cells/mcl (IQR 538-988). Consequently, the CD4/CD8 ratio varied from 0.93 (IQR 0.60-1.30) to 1.15 (IQR 0.77-1.45) (P < 0.0001). A non-significant (P = 0.320) increment of mean creatinine, 0.06 mg/dl in magnitude, was observed over the whole follow-up. CONCLUSION: These long-term results over 5 years reinforce the durability and good tolerability of DTG-3TC. Our results continue to support the recommended switch use of this 2DR as a well-accepted treatment option for ART-experienced PLWH.

Phylogeography and genomic epidemiology of SARS-CoV-2 in Italy and Europe with newly characterized Italian genomes between February-June 2020.

The aims of this study were to characterize new SARS-CoV-2 genomes sampled all over Italy and to reconstruct the origin and the evolutionary dynamics in Italy and Europe between February and June 2020. The cluster analysis showed only small clusters including < 80 Italian isolates, while most of the Italian strains were intermixed in the whole tree. Pure Italian clusters were observed mainly after the lockdown and distancing measures were adopted. Lineage B and B.1 spread between late January and early February 2020, from China to Veneto and Lombardy, respectively. Lineage B.1.1 (20B) most probably evolved within Italy and spread from central to south Italian regions, and to European countries. The lineage B.1.1.1 (20D) developed most probably in other European countries entering Italy only in the second half of March and remained localized in Piedmont until June 2020. In conclusion, within the limitations of phylogeographical reconstruction, the estimated ancestral scenario suggests an important role of China and Italy in the widespread diffusion of the D614G variant in Europe in the early phase of the pandemic and more dispersed exchanges involving several European countries from the second half of March 2020.

Impact of resistance mutations on efficacy of dolutegravir plus rilpivirine or plus lamivudine as maintenance regimens: a cohort study.

OBJECTIVES: The aim of this study was to evaluate the impact of resistance mutations on efficacy of dolutegravir-based two-drug regimens (2DR). METHODS: Virologically suppressed patients with HIV-1 switching to dolutegravir + lamivudine or rilpivirine or to a dolutegravir-based three-drug regimen (3DR) with pre-baseline genotype were selected. Virological failure (VF) was defined as one HIV-RNA viral load (VL) >200 cps/mL or two consecutive VL >50 cps/mL; treatment failure (TF) was defined as VF or treatment discontinuation (TD). Resistance was defined as at least low-level resistance to at least one drug of the current regimen. Propensity score matching was used to conduct adjusted analyses within a competing risks framework. RESULTS: A total of 971 dolutegravir-based regimens were selected: 339 (34.9%) 2DR and 632 (65.1%) 3DR. The adjusted cumulative 48-week incidence of VF was 4.2% (90% CI 3.1%-5.3%) with 2DR and 4.7% (90% CI 3.5%-5.8%) with 3DR. The cumulative 48-week incidence of TF was 15.8% (90% CI 13.9%-17.9%) with 2DR and 24.5% (90% CI 22.2%-27.0%) with 3DR. For VF, the estimated hazard ratio (HR) for 2DR vs. 3DR was 1.02 (90% CI: 0.78-1.34), with evidence of effect modification by low-level resistance (HR 3.96, 90% CI: 2.10-7.46). The estimated HR of TF for 2DR vs. 3DR was 0.54 (90% CI: 0.48-0.60). The 48-week cumulative incidence of TD was 11.7% (8.7%, 14.6%) in 2DR and 19.6% (16.9%, 22.4%) in 3DR. CONCLUSIONS: Dolutegravir-based 2DR showed high virological efficacy and durability; however, past resistance increased the risk of VF, but not of TD or TF.

RNAscope in situ hybridization and RT-PCR for detection of SARS-CoV-2 in chilblain-like lesions: A clinical, laboratory and histopathological study.

BACKGROUND: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, an increasing number of chilblain-like lesions (ChLL) have been increasingly reported worldwide. To date, the causal link between ChLL and SARS-CoV-2 infection has not been unequivocally established. METHODS: In this case series, we present demographic, clinical, laboratory, and histopathological information regarding 27 young patients with a clinical diagnosis of ChLL who referred to the Dermatology Unit of Papa Giovanni XXIII Hospital, Bergamo, Italy, from 1 April 2020 to 1 June 2020. RESULTS: The mean age was 14.2 years, and 21 patients (78%) experienced mild systemic symptoms a median of 28 days before the onset of cutaneous lesions. ChLL mostly involved the feet (20 patients - 74%). Among acral lesions, we identified three different clinical patterns: (i) chilblains in 20 patients (74%); (ii) fixed erythematous macules in 4 children (15%); (iii) erythrocyanosis in 3 female patients (11%). Blood examinations and viral serologies, including parvovirus B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and coxsackievirus were normal in all. Three patients (11%) underwent nasopharyngeal swab for RT-PCR for SARS-CoV-2 showing only 1 positive. Histopathological examinations of 7 skin biopsies confirmed the clinical diagnosis of chilblains; vessel thrombi were observed only in 1 case. Our findings failed to demonstrate the direct presence of SARS-CoV-2 RNA in skin biopsies, both with real-time polymerase chain reaction (RT-PCR) and RNAscope in situ hybridization (ISH). LIMITATIONS: Limited number of cases, unavailability of laboratory confirmation of COVID-19 in all patients, potential methodological weakness, and latency of skin biopsies in comparison to cutaneous lesions onset. CONCLUSIONS: These observations may support the hypothesis of an inflammatory pathogenesis rather than the presence of peripheral viral particles. Although, we could not exclude an early phase of viral endothelial damage followed by an IFN-I or complement-mediated inflammatory phase. Further observations on a large number of patients are needed to confirm this hypothesis.

Circulating SARS-CoV-2 variants in Italy, October 2020-March 2021.

A growing number of emerging SARS-CoV-2 variants is being identified worldwide, potentially impacting the effectiveness of current vaccines. We report the data obtained in several Italian regions involved in the SARS-CoV-2 variant monitoring from the beginning of the epidemic and spanning the period from October 2020 to March 2021.

Covid-19 and gender: lower rate but same mortality of severe disease in women-an observational study.

BACKGROUND: Gender-related factors might affect vulnerability to Covid-19. The aim of this study was to describe the role of gender on clinical features and 28-day mortality in Covid-19 patients. METHODS: Observational study of Covid-19 patients hospitalized in Bergamo, Italy, during the first three weeks of the outbreak. Medical records, clinical, radiological and laboratory findings upon admission and treatment have been collected. Primary outcome was 28-day mortality since hospitalization. RESULTS: 431 consecutive adult patients were admitted. Female patients were 119 (27.6%) with a mean age of 67.0 ± 14.5 years (vs 67.8 ± 12.5 for males, p = 0.54). Previous history of myocardial infarction, vasculopathy and former smoking habits were more common for males. At the time of admission PaO2/FiO2 was similar between men and women (228 [IQR, 134-273] vs 238 mmHg [150-281], p = 0.28). Continuous Positive Airway Pressure (CPAP) assistance was needed in the first 24 h more frequently in male patients (25.7% vs 13.0%; p = 0.006). Overall 28-day mortality was 26.1% in women and 38.1% in men (p = 0.018). Gender did not result an independent predictor of death once the parameters related to disease severity at presentation were included in the multivariable analysis (p = 0.898). Accordingly, the Kaplan-Meier survival analysis in female and male patients requiring CPAP or non-invasive ventilation in the first 24 h did not find a significant difference (p = 0.687). CONCLUSION: Hospitalized women are less likely to die from Covid-19; however, once severe disease occurs, the risk of dying is similar to men. Further studies are needed to better investigate the role of gender in clinical course and outcome of Covid-19.

Antibody response to SARS-CoV-2 vaccination is extremely vivacious in subjects with previous SARS-CoV-2 infection.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic calls for rapid actions, now principally oriented to a world-wide vaccination campaign. In this study we verified if, in individuals with a previous SARS-CoV-2 infection, a single dose of messenger RNA (mRNA) vaccine would be immunologically equivalent to a full vaccine schedule in naïve individuals. Health care workers (184) with a previous SARS-CoV-2 infection were sampled soon before the second dose of vaccine and between 7 and 10 days after the second dose, the last sampling time was applied to SARS-CoV-2 naïve individuals, too. Antibodies against SARS-CoV-2 were measured using Elecsys Anti-SARS-CoV-2 S immunoassay. The study was powered for non-inferiority. We used non parametric tests and Pearson correlation test to perform inferential analysis. After a single vaccine injection, the median titer of specific antibodies in individuals with previous coronavirus disease 2019 was 30.527 U/ml (interquartile range [IQR]: 19.992-39.288) and in subjects with previous SARS-CoV-2 asymptomatic infection was 19.367.5 U/ml (IQR: 14.688-31.353) (p = .032). Both results were far above the median titer in naïve individuals after a full vaccination schedule: 1974.5 U/ml (IQR: 895-3455) (p < .0001). Adverse events after vaccine injection were more frequent after the second dose of vaccine (mean: 0.95; 95% confidence interval [CI]: 0.75-1.14 vs. mean: 1.91; 95% CI: 1.63-2.19) (p < .0001) and in exposed compared to naïve (mean: 1.63; 95% CI: 1.28-1.98 vs. mean: 2.35; 95% CI: 1.87-2.82) (p = .015). In SARS-CoV-2 naturally infected individuals a single mRNA vaccine dose seems sufficient to reach immunity. Modifying current dosing schedules would speed-up vaccination campaigns.

SARS-CoV-2 infection in persons living with HIV: A single center prospective cohort.

Information about severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in HIV-infected individuals is scarce. In this prospective study, we included HIV (human immunodefeciency virus)-infected individuals (people living with HIV [PLWHIV]) with confirmed SARS-CoV-2 infection and compared them with PLWHIV negative for SARS-CoV-2. We compared 55 cases of SARS-CoV-2 infection with 69 asymptomatic PLWHIV negative for SARS-CoV-2 reverse transcription-polymerase chain reaction and/or serology. There was no significant difference between SARS-CoV-2 positive or negative patients for age distribution, gender, time with HIV infection, nadir CD4-cell counts, type and number of co-morbidities, current CD4 and CD8 counts and type of anti-HIV therapy. Positive patients presented with a median of three symptoms (interquartile range, 1-3). Most common symptoms were fever (76%), dyspnea (35%), anosmia (29%) non-productive cough (27%), fatigue 22%), and ageusia (20%). Ten patients (18%) were completely asymptomatic. Four (7.2%) subjects died of coronavirus disease 2019. Factors significantly (P < .05) associated with death included age and number of co-morbidities, while time from HIV infection and lower current CD4 counts were significant only in univariate analysis. HIV-infected individuals are not protected from SARS-CoV-2 infection or have a lower risk of severe disease. Indeed, those with low CD4 cell counts might have worse outcomes. Infection is asymptomatic in a large proportion of subjects and this is relevant for epidemiological studies.

Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.

OBJECTIVES: Evidences from either small series or spontaneous reporting are accumulating that SARS-CoV-2 involves the Nervous Systems. The aim of this study is to provide an extensive overview on the major neurological complications in a large cohort of COVID-19 patients. METHODS: Retrospective, observational analysis on all COVID-19 patients admitted from February 23rd to April 30th, 2020 to ASST Papa Giovanni XXIII, Bergamo, Italy for whom a neurological consultation/neurophysiological assessment/neuroradiologic investigation was requested. Each identified neurologic complication was then classified into main neurologic categories. RESULTS: Of 1760 COVID-19 patients, 137 presented neurologic manifestations that manifested after COVID-19 symptoms in 98 pts and was the presenting symptom in 39. Neurological manifestations were classified as: (a) cerebrovascular disease [53 pts (38.7%)] including 37 ischemic and 11 haemorrhagic strokes, 4 transient ischemic attacks, 1 cerebral venous thrombosis; (b) peripheral nervous system diseases [31 (22.6%)] including 17 Guillain-Barrè syndromes; (c) altered mental status [49 (35.8%)] including one necrotizing encephalitis and 2 cases with RT-PCR detection of SARS-Cov-2 RNA in CSF; (d) miscellaneous disorders, among whom 2 patients with myelopathy associated with Ab anti-SARS-CoV-2 in CSF. Patients with peripheral nervous system involvement had more frequently severe ARDS compared to patients with cerebrovascular disease (87.1% vs 42%; difference = 45.1% 95% CI 42.0-48.2; χ2= 14.306; p < 0.0002) and with altered mental status (87.1% vs 55.6%; difference = 31.5% 95% CI 27.5-37.5%; χ2= 7.055; p < 0.01). CONCLUSION: This study confirms that involvement of nervous system is common in SARS-CoV-2 infection and offers clinicians useful information for prevention and prompt identification in order to set the adequate therapeutic strategies.

At the peak of COVID-19 age and disease severity but not comorbidities are predictors of mortality: COVID-19 burden in Bergamo, Italy.

BACKGROUND: Findings from February 2020, indicate that the clinical spectrum of COVID-19 can be heterogeneous, probably due to the infectious dose and viral load of SARS-CoV-2 within the first weeks of the outbreak. The aim of this study was to investigate predictors of overall 28-day mortality at the peak of the Italian outbreak. METHODS: Retrospective observational study of all COVID-19 patients admitted to the main hospital of Bergamo, from February 23 to March 14, 2020. RESULTS: Five hundred and eight patients were hospitalized, predominantly male (72.4%), mean age of 66±15 years; 49.2% were older than 70 years. Most of patients presented with severe respiratory failure (median value [IQR] of PaO2/FiO2: 233 [149-281]). Mortality rate at 28 days resulted of 33.7% (N.=171). Thirty-nine percent of patients were treated with continuous positive airway pressure (CPAP), 9.5% with noninvasive ventilation (NIV) and 13.6% with endotracheal intubation. 9.5% were admitted to Semi-Intensive Respiratory Care Unit, and 18.9% to Intensive Care Unit. Risk factors independently associated with 28-day mortality were advanced age (≥78 years: odds ratio [OR], 95% confidence interval [CI]: 38.91 [10.67-141.93], P<0.001; 70-77 years: 17.30 [5.40-55.38], P<0.001; 60-69 years: 3.20 [1.00-10.20], P=0.049), PaO2/FiO2<200 at presentation (3.50 [1.70-7.20], P=0.001), need for CPAP/NIV in the first 24 hours (8.38 [3.63-19.35], P<0.001), and blood urea value at admission (1.01 [1.00-1.02], P=0.015). CONCLUSIONS: At the peak of the outbreak, with a probable high infectious dose and viral load, older age, the severity of respiratory failure and renal impairment at presentation, but not comorbidities, are predictors of 28-day mortality in COVID-19.

Prevalence and factors associated with HIV-1 multi-drug resistance over the past two decades in the Italian ARCA database.

Despite successful antiretroviral therapy (ART), patients infected with human immunodeficiency virus (HIV) can develop multi-class drug resistance (MDR). This retrospective study aimed to explore the prevalence of HIV-1 drug resistance over the past two decades by focusing on HIV-MDR and its predictors. ART-experienced patients with HIV with results from at least one plasma genotypic resistance test (GRT) from 1998 to 2018, from the Antiviral Response Cohort Analysis database, were included in this study. The temporal trend of resistance to any drug class was evaluated by considering all GRTs. Prevalence and predictors of HIV-MDR were analysed by consideration of cumulative GRTs. Among 15 628 isolates from 6802 patients, resistance to at least one drug class decreased sharply from 1998 to 2010 (1998-2001: 78%; 2008-2010: 59%; P<0.001) and then remained relatively constant at approximately 50% from 2011 to 2018, with the proportion of isolates with HIV-MDR also stable (approximately 9%). By evaluating factors associated with cumulative HIV-MDR, the following factors were found to be associated with increased risk of HIV-MDR on multi-variate analysis: male gender; sexual and vertical transmission; number of previous protease inhibitors, nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-NRTIs; previous exposure to integrase strand transfer inhibitors, enfuvirtide and maraviroc; and co-infection with hepatitis B virus. In contrast, a nadir CD4 cell count ≥200 cells/mm3, starting first-line ART in 2008 or later and co-infection with hepatitis C virus were associated with lower risk of HIV-MDR. In conclusion, this study revealed that HIV-1 drug resistance has been stable since 2011 despite its dramatic decrease over the past two decades. HIV-MDR is still present, although at a lower rate, suggesting the need for continuous surveillance and accurate management of ART-experienced patients with HIV.

Prevalence and Clinical Impact of SARS-CoV-2 Silent Carriers Among Actively Treated Patients with Cancer During the COVID-19 Pandemic.

INTRODUCTION: In Europe, the SARS-CoV-2 pandemic had its first epicenter in Italy. Despite a significant mortality rate, the severity of most cases of COVID-19 infection ranges from asymptomatic to mildly symptomatic, and silent infection affects a still-unknown proportion of the general population. No information is available on the prevalence and clinical impact of SARS-CoV-2 silent infection among patients with cancer receiving anticancer treatment during the pandemic. MATERIALS AND METHODS: From April 1, 2020, to the end of the same month, 560 consecutive patients with cancer, asymptomatic for COVID-19 and on anticancer treatment at Papa Giovanni XXIII Hospital in Bergamo, were evaluated and tested for SARS-CoV-2. We implemented a two-step diagnostics, including the rapid serological immunoassay for anti-SARS-CoV-2 immunoglobulin (Ig) G/IgM and the nasopharyngeal swab reverse transcriptase-polymerase chain reaction (RT-PCR) test in case of seropositivity to identify SARS-CoV-2 silent carriers. RESULTS: In 560 patients, 172 (31%) resulted positive for anti-SARS-CoV-2 IgM/IgG antibodies, regardless of different type of cancer, stage, and treatment. The Ig-seropositive patients were then tested with RT-PCR nasopharyngeal swabs, and 38% proved to be SARS-CoV-2 silent carriers. At an early follow-up, in the 97 SARS-CoV-2-seropositive/RT-PCR-negative patients who continued their anticancer therapies, only one developed symptomatic COVID-19 illness. CONCLUSION: Among patients with cancer, the two-step diagnostics is feasible and effective for SARS-CoV-2 silent carriers detection and might support optimal cancer treatment strategies at both the individual and the population level. The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in cases of RT-PCR-negative patients. IMPLICATIONS FOR PRACTICE: This is the first study evaluating the prevalence and clinical impact of SARS-CoV-2 silent infection in actively treated patients with cancer, during the epidemic peak in one of the worst areas of the COVID-19 pandemic. Lacking national and international recommendations for the detection of asymptomatic SARS-CoV-2 infection, a pragmatic and effective two-step diagnostics was implemented to ascertain SARS-CoV-2 silent carriers. In this series, consisting of consecutive and unselected patients with cancer, the prevalence of both SARS-CoV-2-seropositive patients and silent carriers is substantial (31% and 10%, respectively). The early safety profile of the different anticancer therapies, in patients previously exposed to SARS-CoV-2, supports the recommendation to continue the active treatment, at least in case of RT-PCR-negative patients.

Composition of the immunoglobulin G glycome associates with the severity of COVID-19.

A large variation in the severity of disease symptoms is one of the key open questions in coronavirus disease 2019 (COVID-19) pandemics. The fact that only a small subset of people infected with severe acute respiratory syndrome coronavirus 2 develops severe disease suggests that there have to be some predisposing factors, but biomarkers that reliably predict disease severity have not been found so far. Since overactivation of the immune system is implicated in a severe form of COVID-19 and the immunoglobulin G (IgG) glycosylation is known to be involved in the regulation of different immune processes, we evaluated the association of interindividual variation in IgG N-glycome composition with the severity of COVID-19. The analysis of 166 severe and 167 mild cases from hospitals in Spain, Italy and Portugal revealed statistically significant differences in the composition of the IgG N-glycome. The most notable difference was the decrease in bisecting N-acetylglucosamine in severe patients from all three cohorts. IgG galactosylation was also lower in severe cases in all cohorts, but the difference in galactosylation was not statistically significant after correction for multiple testing.

Prevalence of resistance-associated substitutions and retreatment of patients failing a glecaprevir/pibrentasvir regimen.

OBJECTIVES: To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir. METHODS: Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated. RESULTS: We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available. CONCLUSIONS: One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes.

Longitudinal Immune Phenotype Assessment and Serological Outcome in Foreign-born Children With Chronic Hepatitis B.

OBJECTIVES: The aim of the study was to assess changes in clinical phenotype, and identify determinants of outcome in children with chronic hepatitis B virus (HBV) infection born in HBV-endemic countries followed in 2 Italian tertiary care centers after immigration or adoption. METHODS: A prospective observational study on hepatitis B e-antibodies-negative chronic hepatitis B children started on 2002. Patients with liver fibrosis, or those needing antiviral treatment were excluded. Immune active patients were defined those with raised transaminases (alanine aminotransferase > 40 IU/L), immune tolerants those having normal alanine aminotransferase, both exhibiting substantial viral replication (HBV DNA >2000 IU/mL). RESULTS: Sixty-nine patients (44 boys, median age 4.7 years) had a median follow-up of 53 months. At entry, 18 (26%) children were immune tolerant, 47 (68%) immune active, and 4 had indeterminant immune status. At last follow-up, 14 (78%) of the immune-tolerant patients remained so, whereas only 23 (49%) of the immune active children maintained their initial immune phenotype. Seroconversion to hepatitis B e antibodies (SCHBe) occurred in only 2 (11%) immune tolerants, whereas 13 (28%) immune active patients achieved SCHBe.Ethnicity was the only feature independently correlated to SCHBe: Asian origin reduced by 4.1 times the probability of SCHBe (Asian vs other; odds ratio = 0.24 [95% confidence interval = 0.07-0.76]; P = 0.016) compared to other ethnicities, whereas viral genotype did not influence the outcome. CONCLUSIONS: Ethnicity and immune status phenotype against HBV, rather than HBV genotype, are the main determinants of SCHBe in foreign-born children with chronic HBV infection.