High-Risk Neutropenic Fever and Invasive Fungal Diseases in Patients with Hematological Malignancies.

Invasive fungal diseases (IFDs) still represent a relevant cause of mortality in patients affected by hematological malignancies, especially acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) undergoing remission induction chemotherapy, and in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Mold-active antifungal prophylaxis (MAP) has been established as a standard of care. However, breakthrough IFDs (b-IFDs) have emerged as a significant issue, particularly invasive aspergillosis and non-Aspergillus invasive mold diseases. Here, we perform a narrative review, discussing the major advances of the last decade on prophylaxis, the diagnosis of and the treatment of IFDs in patients with high-risk neutropenic fever undergoing remission induction chemotherapy for AML/MDS and allo-HSCT. Then, we present our single-center retrospective experience on b-IFDs in 184 AML/MDS patients undergoing high-dose chemotherapy while receiving posaconazole (n = 153 induction treatments, n = 126 consolidation treatments, n = 60 salvage treatments). Six cases of probable/proven b-IFDs were recorded in six patients, with an overall incidence rate of 1.7% (6/339), which is in line with the literature focused on MAP with azoles. The incidence rates (IRs) of b-IFDs (95% confidence interval (95% CI), per 100 person years follow-up (PYFU)) were 5.04 (0.47, 14.45) in induction (n = 2), 3.25 (0.0013, 12.76) in consolidation (n = 1) and 18.38 (3.46, 45.06) in salvage chemotherapy (n = 3). Finally, we highlight the current challenges in the field of b-IFDs; these include the improvement of diagnoses, the expanding treatment landscape of AML with molecular targeted drugs (and related drug-drug interactions with azoles), evolving transplantation techniques (and their related impacts on IFDs' risk stratification), and new antifungals and their features (rezafungin and olorofim).

Impact of predicted HLA class I immunopeptidome on viral reservoir in a cohort of people living with HIV in Italy.

The class I HLA genotype has been widely recognized as a factor influencing HIV disease progression in treatment-naïve subjects. However, little is known regarding its role in HIV disease course and how it influences the size of the viral reservoir once anti-retroviral therapy (ART) is started. Here, leveraging on cutting-edge bioinformatic tools, we explored the relationship between HLA class I and the HIV reservoir in a cohort of 90 people living with HIV (PLWH) undergoing ART and who achieved viral suppression. Analysis of HLA allele distribution among patients with high and low HIV reservoir allowed us to document a predominant role of HLA-B and -C genes in regulating the size of HIV reservoir. We then focused on the analysis of HIV antigen (Ag) repertoire, by investigating immunogenetic parameters such as the degree of homozygosity, HLA evolutionary distance and Ag load. In particular, we used two different bioinformatic algorithms, NetMHCpan and MixMHCpred, to predict HLA presentation of immunogenic HIV-derived peptides and identified HLA-B*57:01 and HLA-B*58:01 among the highest ranking HLAs in terms of total load, suggesting that their previously reported protective role against HIV disease progression might be linked to a more effective viral recognition and presentation to Cytotoxic T lymphocytes (CTLs). Further, we speculated that some peptide-HLA complexes, including those produced by the interaction between HLA-B*27 and the HIV Gag protein, might be particularly relevant for the efficient regulation of HIV replication and containment of the HIV reservoir. Last, we provide evidence of a possible synergistic effect between the CCR5 ∆32 mutation and Ag load in controlling HIV reservoir.

Viral Hepatitis and Human Papillomavirus Vaccination During HIV Pre-Exposure Prophylaxis: Factors Associated With Missed Vaccination.

BACKGROUND: We evaluated factors associated with lack of triple vaccination (hepatitis A virus [HAV], hepatitis B virus [HBV], and human papillomavirus [HPV]) among men who have sex with men using pre-exposure prophylaxis (PrEP). SETTING: PrEP users at the San Raffaele Scientific Institute, Italy, with ≥1 follow-up visit (May 2017-2022). METHODS: Participants were considered protected if (1) before PrEP access: positive serology (IgG-HAV+, hepatitis B surface antigen >10 mUI/mL) or vaccination history was recorded and (2) after starting PrEP: ≥1 dose of each vaccination was administered. Individuals were considered fully protected if they received the following before/during PrEP access: HAV vaccination/infection, HBV vaccination/infection, and HPV vaccination. χ 2 and Kruskal-Wallis tests were used to compare characteristics of those fully, partially, and not protected. Factors associated with the lack of triple vaccination were assessed by using multivariable logistic regression and classification tree analysis. RESULTS: Overall, 473 men who have sex with men were considered: 146 (31%) were fully protected, 231 (48%) partially, and 96 (20%) were not. Daily-based PrEP users (fully: 93, 63.7%; partially: 107, 46.3%; and not protected: 40, 41.7%; P = 0.001) and those with a sexually transmitted infection at the first visit (43, 29.5%; 55, 23.8%; 15, 15.6%; P = 0.048) were more frequently fully protected. At multivariable analysis, the odds of lack of triple vaccination was lower among daily-based users (adjusted odds ratio = 0.47, 95% confidence interval = 0.31-0.70, P < 0.001). Classification tree analysis showed that among daily-based users, with sexually transmitted infection prior and at the first PrEP visit, there was a lower chance of lack of triple vaccination ( P = 44%). CONCLUSIONS: Strategies targeting PrEP users at risk of missing HAV, HBV, and HPV vaccinations need to be implemented, focusing mostly on event-based users.

Survival in People Living with HIV with or without Recurrence of Hepatocellular Carcinoma after Invasive Therapy.

BACKGROUND AND AIMS: To address the overall survival (OS) and recurrence (RE) in people living with HIV (PLWH) treated with invasive therapy (IT) for hepatocellular carcinoma (HCC). METHODS: This is a retrospective cohort study on 41 PLWH with HCC receiving IT, defined as liver resection (LR), orthotopic liver transplantation (OLT), radiofrequency thermo-ablation (RFTA) trans arterial chemo, or radioembolization (CRE). OS and RE were investigated by Kaplan-Meier curves. The Cox proportional hazard regression model was used for multivariate analyses. RESULTS: Recurrence occurred in 46.3% PLWH; in 36.7% of participants at 2 years and in 52% at 5 years from HCC diagnosis; it was less frequent in males, p = 0.036. Overall, 2- and 5-year survival after HCC diagnosis was 72% and 48%, respectively. Two-and five-year survival was 100% and 90.9%, respectively, in PLWH receiving OLT, compared to other IT (60.9% and 30.6%, respectively) log-rank p = 0.0006. Two- and five-year survival in participants with no-RE was 70.5% and 54.6%, respectively, and 73.7% and 42.1% among RE, respectively, log-rank p = 0.7772. By multivariate analysis, AFP at values < 28.8 ng/mL, at HCC diagnosis, was the only factor predicting survival. CONCLUSIONS: Fifty percent of PLWH survived five years after HCC diagnosis; 90.9% among OLT patients. Recurrence after IT was observed in 46% of HCC/PLWH. AFP cut-off levels of 28.8 ng/mL were the only independent variable associated with survival.

Inflammation burden score in multidrug-resistant HIV-1 infection.

OBJECTIVES: Four-class drug-resistant (4DR) people living with HIV (PLWH) are a fragile population with a high burden of disease. No data on their inflammation and T-cell exhaustion markers are currently available. METHODS: Inflammation, immune activation and microbial translocation biomarkers were measured through ELISA in 30 4DR-PLWH with HIV-1 RNA ≥ 50 copies/mL, 30 non-viremic 4DR-PLWH and 20 non-viremic non-4DR-PLWH. Groups were matched by age, gender and smoking habit. T-cell activation and exhaustion markers were assessed by flow cytometry in 4DR-PLWH. An inflammation burden score (IBS) was calculated from soluble marker levels and associated factors were estimated through multivariate regression. RESULTS: The highest plasma biomarker concentrations were observed in viremic 4DR-PLWH, the lowest ones in non-4DR-PLWH. Endotoxin core immunoglobulin G showed an opposite trend. Among 4DR-PLWH, CD38/HLA-DR and PD-1 were more expressed on CD4+ (p = 0.019 and 0.034, respectively) and CD8+ (p = 0.002 and 0.032, respectively) cells of viremic compared to non-viremic subjects. An increased IBS was significantly associated with 4DR condition, higher values of viral load and a previous cancer diagnosis. CONCLUSIONS: Multidrug-resistant HIV infection is associated with a higher IBS, even when viremia is undetectable. Therapeutic approaches aimed to reduce inflammation and T-cell exhaustion in 4DR-PLWH need to be investigated.

Meningococcus B Vaccination Effectiveness Against Neisseria gonorrhoeae Infection in People Living With HIV: A Case-Control Study.

BACKGROUND: We assessed the vaccination effectiveness (VE) of multicomponent meningococcal serogroup B (4CMenB) vaccine against gonorrhea among people living with HIV (PLWH) with a previous diagnosis of sexually transmitted infection. METHODS: Unmatched case-control study on men who have sex with men living with HIV, in care at San Raffaele Scientific Institute, Milan, Italy, with gonorrhea, syphilis, chlamydia, or anal human papillomavirus between July 2016 (beginning of 4CMenB vaccination) and February 2021 (date of freezing). For the analysis, cases were people with ≥1 gonorrhea infection since July 2016, and controls were people with ≥1 syphilis, chlamydia, or anal human papillomavirus infection since July 2016. Logistic regression was used to provide the estimate of 4CMenB VE against gonorrhea. RESULTS: Included people living with HIV were 1051 (103 cases, 948 controls); 349 of 1051 (33%) received 2 doses of 4CMenB vaccination. The median follow-up was 3.8 years (2.1-4.3 years). The unadjusted estimate for VE against gonorrhea was 42% (95% confidence interval, 6%-64%; P = 0.027). Logistic regression showed that VE against gonorrhea remained significant (44%; 95% confidence interval, 9%-65%; P = 0.020) after adjusting for some factors that might have a potential influence on VE or those with significant unbalanced distributions between cases and controls at univariable analysis. CONCLUSIONS: 4CMenB vaccination is associated with a lower risk of gonorrhea in the setting of men who have sex with men living with HIV with a previous sexually transmitted infection.

Levofloxacin prophylaxis vs no prophylaxis in patients with neutropenia within an endemic country for carbapenem-resistant GNB.

Fluoroquinolone prophylaxis's (FQ-P) usefulness in patients with neutropenia is controversial. In recent decades, Italian epidemiological data has shown worrisome rates of FQ resistance. A single-center cohort study on 136 autologous stem cell transplantations (ASCTs) and 223 allogeneic hematopoietic stem cell transplantations (allo-HSCTs) was performed from January 2018 to December 2020. Piperacillin/tazobactam was the first-line therapy for febrile neutropenia (FN). Since February 2019, FQ-P has been omitted. We evaluated the day +30 posttransplant cumulative incidence function (CIF) of gram-negative bacteria pre-engraftment bloodstream infections (PE-BSIs) and any changes in antimicrobial resistance, FN, and infection-related mortality (IRM). In ASCTs, ≥1 FN episode occurred in 74.3% of transplants, without differences among groups (P = .66). CIF of gram-negative bacteria PE-BSI was 10.1%, with a significant difference according to FQ-P (0% [LEVO-group] vs 14.1% [NO-LEVO-group], P = .016). CIF of IRM was 0% in both groups. In allo-HSCTs, ≥1 FN episode occurred in 96.4% of transplants, without differences among groups (P = .72). CIF of gram-negative bacteria PE-BSI was 28%, significantly higher without FQ-P (14.7% [LEVO-group] vs 34.4% [NO-LEVO-group], P = .003). CIF of IRM was 5%, superimposable in both groups (P = .62). Comparing antimicrobial resistance among gram-negative bacteria of allo-HSCT setting, in the group without FQ-P, a significantly higher proportion of pathogens was susceptible to piperacillin/tazobactam (71% vs 30%, P = .026), FQ (49% vs 10%, P = .03), and carbapenems (95% vs 50%, P = .001). FQ-P discontinuation increased gram-negative bacteria PE-BSI but did not impact IRM, both in the ASCT and allo-HSCT settings; importantly, it concurred to significantly decrease antimicrobial resistance in gram-negative bacteria.

Association of high-risk sexual behaviours with sexually transmitted infections among men who have sex with men living with HIV.

OBJECTIVES: To explore different sexual behaviours as risk factors for STI among men who have sex with men (MSM) living with HIV. METHODS: This is a cross-sectional study on MSM living with HIV followed at the Infectious Diseases Unit of San Raffaele Hospital, Milan, with at least one diagnosis of gonorrhoea, syphilis, chlamydia or anal human papilloma virus (HPV), between July 2016 and February 2021. We conducted a survey on high-risk sexual behaviours with regard to (1) mean number of partners per month, (2) estimated percentage of condom use and (3) most frequent type of sexual intercourse during 2016-2021. Data on these variables were grouped as follows: (1a) ≤5 vs >5, (1b) >10 vs ≤10, (2a) 0% vs >0%, (2b) ≤50% vs >50%, (2c) 100% vs <100%, (3a) ≥50% vs <50% receptive, (3b) 100% vs <100% insertive, and (3c) 100% vs <100% receptive. A high-risk group was defined as >5 partners, <100% use of condom and ≥50% receptive intercourse. Univariate logistic regressions were applied to assess the association between sexual behaviours and the risk of each STI. RESULTS: Out of 1051 MSM with at least one STI diagnosis, 580 (55%) answered the survey. The risk of chlamydia was lower among individuals with ≤5 partners (≤5 partners vs >5 partners: OR=0.43, 95% CI 0.28 to 0.66, p=0.001) and among those using condoms more frequently (≤50% use of condom vs >50% use of condom: OR=1.55, 95% CI 1.06 to 2.27, p=0.025; 100% vs <100%: OR=0.35, 95% CI 0.20 to 0.59, p=0.001). Individuals using condoms more frequently also had lower risk of gonorrhoea (100% use of condom vs <100% use of condom: OR=0.37, 95% CI 0.17 to 0.79, p=0.011). The risks of chlamydia (OR=3.07, 95% CI 1.92 to 4.90, p<0.001) and gonorrhoea (OR=2.05, 95% CI 1.12 to 3.75, p=0.020) were higher among individuals belonging to the high-risk group. CONCLUSIONS: Chlamydia and gonorrhoea are more likely associated with high-risk sexual behaviours than syphilis and anal HPV among MSM living with HIV.

Vitamin D Supplementation Impacts Systemic Biomarkers of Collagen Degradation and Copper Metabolism in Patients With Keratoconus.

Purpose: To evaluate the impact of vitamin D (Vit D) supplementation on systemic biomarkers of collagen degradation, inflammation, oxidative stress, and copper metabolism in adolescent patients with keratoconus (KC). Methods: This was a prospective observational pilot study. Twenty patients (age range, 16-19 years) presenting KC and Vit D insufficiency (<30 ng/mL) were included. Vit D supplementation was prescribed by their general practitioner as per the standard of care. Patients were followed up for 12 months. At each visit, best spectacle-corrected visual acuity (BSCVA), maximal keratometry (Kmax), and thinnest corneal thickness (TCT) were evaluated. The primary outcome of the study was the proportion of patients with Kmax progression of less than 1 D throughout the 12-month follow-up time. Blood samples were collected at different time points to evaluate Vit D levels and systemic markers of collagen degradation, inflammation, oxidative stress, and copper metabolism by ELISA or RT-PCR. Results: Lower Vit D levels in the plasma were correlated with higher levels of systemic biomarkers of collagen degradation. Vit D supplementation increased the cell availability of copper. Moreover, stabilization of KC progression was found in 60% of patients (72% of eyes) after 12 months with Vit D supplementation. BSCVA, Kmax, and TCT rates remained stable during the observation period. Conclusions: Our findings support that Vit D administration could affect ocular and systemic biomarkers in KC and illuminate a possible mechanism that can be used to develop new treatment alternatives. Translational Relevance: Although KC therapy currently relies exclusively on surgical procedures, Vit D supplementation may offer a non-invasive and inexpensive alternative with minimal associated side effects.

Prevalence and Risk Factors of Anal HPV Infection in MSM Living With HIV: Identifying the Target Groups to Prioritize for Immunization.

BACKGROUND: Aims of this study are assessing prevalence of anal human papillomavirus (HPV) genotypes in male who have sex with men (MSM) living with HIV over a period of 5 years and determining risk factors for anal infection from high-risk (HR) HPV genotypes or included in vaccine Gardasil 9. SETTING: Time-trend, monocentric study on MSM living with HIV who underwent HPV test at anal site from 2015 to 2019. METHODS: Anal swabs were processed by multiplex real-time polymerase chain reaction to detect HPV genotypes. The Cochran-Armitage test was used to assess linear trend in HPV prevalence over time and logistic regression models to estimate risk factors. RESULTS: Of the 1352 MSM living with HIV, 168 (12%) were not infected by any HPV genotypes and only 6 were infected with a maximum of 6 genotypes; prevalence of HR-HPV genotypes or those included in the 9-valent vaccine remained stable over time. At multivariable analysis, the risk of carrying at least 1 genotype classified as HR or included in Gardasil 9 was associated with younger age [adjusted odds ratio (aOR) for younger than 30 years vs older than 45 years (95% confidence interval) 2.714 (1.484 to 4.961), P = 0.001, and 1.868 (1.141 to 3.060), P < 0.013, respectively] and a history of gonorrhea [aOR 2.118 (1.100 to 4.078), P = 0.025, and 1.785 (1.056 to 3.018), P = 0.031, respectively]. CONCLUSION: Our findings suggest that prevalence remained stable over time and that all MSM with HIV would benefit from Gardasil 9 immunization, particularly the youngest and those with a prior gonococcal infection.

Switching from a Non-Protease inhibitor-Based Regimen To the Fixed Dose Combination of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide in Clinical Practice.

Background: The primary objective of this study was to estimate the proportion of people living with HIV (PLWH) who switched from a non-protease inhibitor (PI)-based regimen [integrase strand transfer inhibitor (InSTI)-based or non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen] to darunavir, cobicistat, emtricitabine, tenofovir alafenamide (D/C/F/TAF). Methods: This was a retrospective study on PLWH treated with a non-PI regimen in January 2017, who switched to D/C/F/TAF or to another antiretroviral therapy (ART) within November 2019. Follow-up was from the start date of D/C/F/TAF until the last available visit or discontinuation for any reason of this regimen. Virological failure (VF) was defined as 2 consecutive HIV-RNA values >50 copies/mL. Characteristics were reported as median (interquartile range) or frequency (%). A univariate Poisson regression model was used to measure the incidence rate of switch to D/C/F/TAF. Changes in laboratory parameters during D/C/F/TAF were assessed by univariate mixed linear models. Results: Overall, 3076 PLWH were included; 83% were male, median age at ART switch was 50 (42-56) years and median time on ART was 5.2 (0.3-13.0) years. PLWH had a median follow-up of 4.76 (3.70-6.38) years; during 17,099 person-years of follow-up (PYFU), 423/3076 (14%) participants discontinued the non-PI-based regimen and 106/423 (25%) switched to D/C/F/TAF, with an overall incidence rate of switch to D/C/F/TAF of 6.2 per 1000-PYFU (95% CI: 5.0-7.4). Among PLWH who switched to D/C/F/TAF, the ongoing regimen was based on NNRTIs in 37 (35%) and on InSTIs in 69 (65%). Main reasons leading to switch to D/C/F/TAF included neuropsychiatric adverse events (37%), VF (26%) and Kaposi sarcoma progression (5%). Conclusion: In the last years, a non-negligible proportion of patients on an NNRTI- or an InSTI-based regimen switched to D/C/F/TAF.

Levels of Alpha-Fetoprotein and Association with Mortality in Hepatocellular Carcinoma of HIV-1-Infected Patients.

METHODS: This is a retrospective cohort study on patients living with HIV-1 infection (PLWH) followed at the Division of Infectious Diseases of the San Raffaele Hospital, with cirrhosis and HCC diagnosed between 1999 and 2018 and with an available AFP value at HCC diagnosis. The area under the receiver operating characteristic curve (AUC) was used to estimate the accuracy of baseline AFP in predicting death. Factors associated with the risk of death were identified using multivariable Cox proportional-hazards regression models. RESULTS: Overall, 53 PLWH were evaluated: 18 patients received a curative treatment (9 liver transplantation, 5 liver resections and 4 radiofrequency ablation) and 35 a noncurative treatment (17 chemo or radio embolization, 10 sorafenib and 8 best supportive care). Baseline AFP was predictive of death [AUC 0.71, 95% confidence interval (CI) 0.54-0.83], and the optimal cut-off was 28.8 ng/mL. At multivariable analysis, BL AFP ≥28.8 ng/mL was associated with death [adjusted hazard ratio (aHR) 7.05, 95% CI 1.94-25.71 P = 0.003]. Other factors were HBV infection (aHR 8.57, 95% CI 1.47-50.08, P = 0.017) and treatment allocation (curative vs. noncurative, aHR 0.08, 95% CI 0.02-0.40, P = 0.0004). CONCLUSIONS: Our findings suggest that in PLWH AFP serum levels ≥28.8 ng/mL, HBV coinfection and treatment allocation represent predictive markers for death at the time of HCC diagnosis.

Viral resistance burden and APOBEC editing correlate with virological response in heavily treatment-experienced people living with multi-drug resistant HIV.

BACKGROUND: The impact of drug resistance mutational load and APOBEC editing in heavily treatment-experienced (HTE) people living with multidrug-resistant HIV has not been investigated. MATERIAL AND METHODS: This study explored the HIV-DNA and HIV-RNA mutational load of drug resistance and APOBEC-related mutations through next-generation sequencing (NGS, Illumina MiSeq) in 20 failing HTE participants enrolled in the PRESTIGIO registry. RESULTS: The patients showed high levels of both HIV-DNA (4.5 [4.0-5.2] log10 copies/106 T-CD4+ cell) and HIV-RNA (4.5 [4.1-5.0] log10 copies/mL) with complex resistance patterns in both compartments. Among the 255 drug-resistant mutations found, 66.3% were concordantly detected in both HIV-DNA and HIV-RNA; 71.3% of mutations were already present in historical Sanger genotypes. At an intra-patient frequency > 5%, a considerable proportion of mutations detected through DNA-NGS were found in historical genotypes but not through RNA-NGS, and few patients had APOBEC-related mutations. Of 14 patients who switched therapy, the five who failed treatment had DNA resistance with higher intra-patient frequency and higher DNA/RNA mutational load in a context of tendentially less pronounced APOBEC editing compared with those who responded. CONCLUSIONS: Using NGS in HIV-DNA and HIV-RNA together with APOBEC editing evaluation might help to identify HTE individuals with MDR who are more prone to experience virological failure.

Exercise ECG for coronary artery disease screening in people living with HIV.

BACKGROUND: Coronary artery disease (CAD) is one of the leading causes of death among people living with HIV (PLWH). We evaluated ECG stress testing (EST) for detecting CAD in PLWH with multiple cardiovascular risk factors. METHODS: CORDIS was a cross-sectional study conducted in PLWH. Inclusion criteria were men at least 50 years or postmenopausal women, HIV-1 RNA less than 50 copies/ml and at least one of the following cardiovascular risk factor: familial history of CAD, smoking, hypertension, hypercholesterolemia or diabetes. Patients with a previous diagnosis of CAD or with cardiac symptoms were excluded. EST was performed concomitantly with bilateral carotid color-Doppler ultrasonography (CDU) and evaluated by a cardiologist. Results were described by median (interquartile range) or frequency (%). Logistic regression was applied to evaluate predictive factors of inducible myocardial ischemia (IMI). RESULTS: EST and CDU were performed in 309 individuals; IMI prevalence was 7.4% [95% confidence interval (CI): 5.0-11.0%]. Among patients with a normal CDU, no cases of IMI were observed. In people with abnormal CDU, IMI prevalence increased accordingly with the atherosclerotic cardiovascular disease (ASCVD) risk score: 10.2%, 16.9%, 19.7%, 27.8% and 30.4% among individuals with ASCVD score 7.5% or less, more than 7.5%, more than 10%, more than 15% and more than 20%, respectively (P for trend: 0.02). At multivariate analysis, ASCVD risk score was associated with EST suggestive of IMI (adjusted odds ratio for 1% increase = 1.08; 95% CI: 1.02-1.13, P = 0.005) and with confirmed IMI (adjusted odds ratio for 1% increase = 1.11; 95% CI: 1.04-1.19, P = 0.003). CONCLUSION: Prevalence of IMI was 7.4% in the CORDIS study. We suggest EST as first-line screening for CAD in PLWH without cardiac symptoms, with an abnormal CDU and a high ASCVD risk score.

Burden of Disease in PWH Harboring a Multidrug-Resistant Virus: Data From the PRESTIGIO Registry.

BACKGROUND: Currently, no data are available on the burden of morbidity and mortality in people with HIV-1 (PWH) harboring a 4-class drug-resistant (4DR) virus (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase strand transfer inhibitors). The study aimed to assess the incidence of clinical events and death in this population. METHODS: This was a cohort study on PWH from the PRESTIGIO Registry with a documented 4DR virus. Burden of disease was defined as the occurrence of any new event including an AIDS-defining event (ADE) or non-AIDS-defining event (NADE) or death from any cause after 4DR evidence (baseline). Cox regression models evaluated factors associated with the risk of new clinical events/death. RESULTS: Among 148 PWH followed for a median (interquartile range) of 47 (32-84) months after 4DR evidence, 38 PWH had 62 new events or died from any cause (incidence rate, 9.12/100 person-years of follow-up; 95% CI = 6.85-11.39): 12 deaths (6 AIDS-related and 6 non-AIDS-related), 18 ADEs, 32 NADEs; 20 of the 38 NADEs (45%) of the incident clinical events were malignancies. The 4-year cumulative incidence of death was 6% (95% CI, 3%-13%), and that of ≥1 event or death was 22% (95% CI, 16%-31%). A higher risk of new clinical events/death was more likely in PWH with previous clinical events (adjusted hazard ratio [aHR], 2.67; 95% CI, 1.07-6.67) and marginally associated with lower baseline CD4+/CD8+ ratio (aHR, 0.82; 95% CI, 0.65-1.02). CONCLUSIONS: PWH harboring 4DR have a high burden of disease with a worrying incidence of malignancies, strongly advising for close prevention and monitoring interventions as well as access to innovative therapeutic strategies, especially in people with a history of clinical events and low CD4+/CD8+ ratio.

Early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy.

BACKGROUND: National health-system hospitals of Lombardy faced a heavy burden of admissions for acute respiratory distress syndromes associated with coronavirus disease (COVID-19). Data on patients of European origin affected by COVID-19 are limited. METHODS: All consecutive patients aged ≥18 years, coming from North-East of Milan's province and admitted at San Raffaele Hospital with COVID-19, between February 25th and March 24th, were reported, all patients were followed for at least one month. Clinical and radiological features at admission and predictors of clinical outcomes were evaluated. RESULTS: Of the 500 patients admitted to the Emergency Unit, 410 patients were hospitalized and analyzed: median age was 65 (IQR 56-75) years, and the majority of patients were males (72.9%). Median (IQR) days from COVID-19 symptoms onset was 8 (5-11) days. At hospital admission, fever (≥ 37.5 °C) was present in 67.5% of patients. Median oxygen saturation (SpO2) was 93% (range 60-99), with median PaO2/FiO2 ratio, 267 (IQR 184-314). Median Radiographic Assessment of Lung Edema (RALE) score was 9 (IQR 4-16). More than half of the patients (56.3%) had comorbidities, with hypertension, coronary heart disease, diabetes and chronic kidney failure being the most common. The probability of overall survival at day 28 was 66%. Multivariable analysis showed older age, coronary artery disease, cancer, low lymphocyte count and high RALE score as factors independently associated with an increased risk of mortality. CONCLUSION: In a large cohort of COVID-19 patients of European origin, main risk factors for mortality were older age, comorbidities, low lymphocyte count and high RALE.

Infections after Allogenic Transplant with Post-Transplant Cyclophosphamide: Impact of Donor HLA Matching.

Incidence and outcome of infections after allogeneic hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PT-Cy) as graft-versus-host disease (GVHD) prophylaxis are largely unknown. Study aims were to estimate the incidence of pre-engraftment bloodstream infections (PE-BSIs) and viral infections (VIs; cytomegalovirus [CMV], adenovirus [ADV], human herpes virus 6 [HHV6], and BK-polyomavirus hemorrhagic-cystitis [BKPyV-HC]), their predictive factors, and infection-related mortality (IRM) after HSCT with PT-Cy. We analyzed 235 patients: 62%, 21%, and 17% received haploidentical (haplo), matched-unrelated donor (MUD), and matched-related donor, respectively. Overall, 72 patients had 77 PE-BSI episodes at a median time of 13 days after HSCT: cumulative incidence function (CIF) at 28 days was 32%, without differences among donor types (P = .988). By multivariate analysis, CIF of PE-BSI was higher in patients with severe neutropenia before HSCT (adjusted hazard ratio [AHR] = 2.90) and in multidrug-resistant Gram-negative bacteria rectal carriers (AHR = 2.68). IRM at 30 days was 5%, without differences by donor type (P = .106). Overall, 208 patients experienced ≥1 VIs (first occurrence among CMV, HHV6, ADV, BKPyV-HC) at a median time of 20 days after HSCT: CIF at 90 days was 91%, significantly higher in MUD and haplo (P = .0089). By multivariate analysis, also acute GVHD grade ≥2 (AHR = 1.32) and host/donor CMV-serology mismatch (positive/positive versus negative/negative: AHR = 2.95, positive/negative versus negative/negative: AHR = 2.41, negative/positive versus negative/negative: AHR = 2.35) affected VIs occurrence. IRM at 180 days was 8%, without differences among donor types (P = .106). In conclusion, study results did not show a significant impact of donor type on PE-BSI incidence; conversely, MUD and haploidentical transplants retained a higher occurrence of VIs in the early phase after HSCT.

Glomerular filtration rate estimated by cystatin C formulas in HIV-1 patients treated with dolutegravir, rilpivirine or cobicistat.

As dolutegravir (DTG), rilpivirine (RPV) and cobicistat affect creatinine, but not cystatin C, tubular transport or serum concentration, the aim of the study was to compare estimated glomerular filtration rates (eGFRs) calculated by means of a standard creatinine formula with those calculated by means of the cystatin C formula in patients receiving these drugs. This was a cross-sectional study of HIV-1 infected patients with eGFR <90 ml/min/1.73 m2 (CKD-EPI-creatinine formula) on-treatment with regimens including DTG, RVP or cobicistat; cystatin C was measured after the switch to these regimens. eGFR was calculated by means of the CKD-EPI formulas (CKD-EPI-creatinine: eGFRcrea; CKD-EPI-cystatin C: eGFRcyst). eGFRcyst was compared with the last eGFR assessed before (eGFRcrea pre) and after the switch (eGFRcrea post). The primary end-point of the study was the difference between eGFRcyst and eGFRcrea post. One hundred and twenty patients were included. eGFRcrea pre was 80 (70-92) ml/min/1.73 m2. eGFRcrea post was significantly lower than eGFRcyst (65 [59-75] vs. 80 [69-95] mL/ min/1.73m2; p<0.001); eGFRcyst did not differ from eGFRcrea pre (p=0.544). The difference between eGFRcyst and eGFRcrea post was not significantly different among regimen groups (p=0.056). In HIV-patients with reduced eGFR treated with DTG, RPV or cobicistat, measuring eGFR by means of the CKD-EPI cystatin C formula is probably more relevant.

Time spent with residual viraemia after virological suppression below 50 HIV-RNA copies/mL according to type of first-line antiretroviral regimen.

PURPOSE: To investigate if the regimen used when starting antiretroviral therapy (ART) affects the time spent with residual viraemia (RV) after achieving <50 HIV-RNA copies/mL. METHODS: Retrospective cohort study on patients infected with human immunodeficiency virus (HIV), followed prospectively, who started ART with a boosted protease inhibitor (PI/r)-, a non-nucleoside reverse transcriptase inhibitor (NNRTI)- or an integrase inhibitor (InSTI)-based triple regimen, or a regimen with more than three drugs. RV was defined as any detectable polymerase chain reaction (PCR) signal <50 HIV-RNA copies/mL, as assessed by kinetic PCR or Abbott real-time PCR. The percentage of time spent with RV (%RV) was calculated as the cumulative follow-up time spent with RV on the observed follow-up, and was estimated using a generalized linear model. RESULTS: Seven hundred and seventy-one patients (33%, 32%, 30% and 5% receiving PI/r-, NNRTI-, InSTI-based triple regimens, or a regimen with more than three drugs, respectively) were included in the analysis. After a median of 2.16 (interquartile range 1.27-3.16) years of follow-up, adjusted means of %RV were 37.9% [95% confidence interval (CI) 30.3-45.4%], 23.9% (95% CI 16-31.8%), 25.3% (95% CI 17.8-32.7%) and 45.5% (95% CI 34.6-56.4%) in the PI/r, NNRTI, InSTI and more than three drugs groups, respectively; %RV was significantly higher in patients who started ART with a regimen with more than three drugs (P=0.030), and was significantly lower in patients who started ART with an NNRTI-based regimen (P<0.0001) or an InSTI-based regimen (P=0.030) than in those who started ART with a PI/r-based regimen. %RV was independently associated with pre-ART HIV-RNA (P<0.0001), time to HIV-RNA <50 copies/mL (P<0.0001), NRTI backbone (P=0.037) and baseline HIV-RNA (P<0.0001). CONCLUSION: First-line regimens based on PIs/r or on more than three drugs are associated with a greater percentage of time spent with RV after achieving virological suppression.