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Background and Objectives: Liver transplantation is now considered a safe procedure in patients with HIV because of the advent of potent antiretroviral therapies (ART). Objective: We aimed to describe the use of dolutegravir-based maintenance ART in patients with HIV and liver transplant regularly followed in our hospital. Methods: We searched the database of our Department of Infectious Diseases for liver transplant recipients receiving calcineurin inhibitor-based maintenance immunosuppression concomitantly treated with dolutegravir for at least 1 month. Results: Ten HIV-positive liver transplant recipients were identified. At 4.6 ± 3.5 years post-transplant, all the patients were switched to dolutegravir-based therapies for treatment simplification. However, at 1 year after the switch, five of the ten patients returned to their previous ART regimens because of increased serum transaminases (n = 1), reversible increased serum creatinine (n = 4), repeated episodes of nausea/vomiting (n = 1) and variable out-of-range concentrations of tacrolimus or cyclosporine (n = 2). However, it should be recognized that these events cannot be unequivocally ascribed to dolutegravir and, in the case of increased serum creatinine, are predictable. Conclusions: The management of HIV-positive liver transplant recipients in clinical practice is a complex task, where possibility of simplifying antiretroviral regimens must be balanced with the need to guarantee optimal immunosuppression and the finest treatment tolerability. A multidisciplinary approach involving physicians and clinical pharmacologists/pharmacists could help achieve this goal. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of a 57-year-old HIV-infected patient who received orthotopic liver transplant and has performed therapeutic drug monitoring (TDM) of raltegravir (RAL) plasma.

A letter to the editor is presented which discusses hepatitis C virus (HCV)-associated cryoglobulinaemic vasculitis.

A letter to the editor is presented in response to the article "Evaluation of drug-drug interactions between hepatitis C antiviral agents ombitasvir, paritaprevir/ritonavir, and dasabuvir and HIV- 1 protease inhibitors" by A. Khatri, S. Dutta and H. Wang in the previous issue.

• Chronic hepatitis C may lead to hypergammaglobulinemia partly due to immune activation. • A rapid decrease of gamma globulins was seen after HCV eradication with antivirals. • HCV-RNA, ALT and fibrosis score levels were associated with gamma globulin decrease. • A role of HCV on B cells activation and gamma globulins production is hypothesized. chronic viral infections by both HCV and HIV may lead to polyclonal activation of B cells resulting in hypergammaglobulinemia. This study retrospectively analyzed the effect of HCV eradication with interferon-free direct-acting antiviral agents (DAAs) on the gamma globulin levels in HCV-infected patients with or without HIV coinfection to identify factors potentially associated with gamma globulins decrease. The charts of patients treated with DAAs for HCV chronic infection between January 2015-June 2019 were retrospectively reviewed. Gamma globulin levels before treatment and 12 weeks after the end of anti-HCV therapy were evaluated along with liver tests, liver fibrosis stage by elastography, SVR achievement, HIV-coinfection. Multivariate analyses were carried out to assess the factors and the potential confounders related to the changes in gamma globulin levels. A significant decrease of gamma globulin concentration was found in both cirrhotic and non-cirrhotic HCV-infected patients after treatment (from mean ± SD of 1.5 ± 0.44 g/dL to 1.31 ± 0.37 g/dL; p = 0.0001). Adjusted linear regression analyses of serum gamma globulin changes from baseline to SVR12 showed a positive significant association with pre-treatment gamma-globulin levels (β-coefficient −0.23; p = 0.0001), Metavir fibrosis score (β-coefficient -0.74; p = 0.008), ALT values and baseline HCV-RNA levels > 800,000. No difference was found between HIV-infected and HIV-uninfected patients. Our study confirms previous preliminary observation of the decrease of serum gamma globulins after HCV eradication either achieved with interferon-based therapy or with DAAs, suggesting a leading role of the virus on the activation of B cell compartment and gamma globulins production. [ABSTRACT FROM AUTHOR]

Purpose: Besides the well-established efficacy in preventing severe COVID-19, the impact of early treatments, namely antivirals and monoclonal antibodies (mAbs), on the time length to negativization of SARS-CoV-2 nasal swabs is still unclear. The aim of this study was to compare the efficacy of different early treatments in reducing the SARS-CoV-2 viral shedding, identifying a single drug that might potentially lead to a more rapid negativization of SARS-CoV-2 nasal swab. Methods: This was a single-centre, retrospective, observational study conducted at Ospedale Luigi Sacco in Milan. Data of high-risk COVID-19 patients who received early treatments between 23 December 2021 and March 2023 were extracted. The comparison across treatments was conducted using the Kruskall-Wallis test for continuous variables. Dunn's test with Bonferroni adjustment was performed for post-hoc comparisons of days to negativization. Secondly, a negative binomial regression adjusted for age, sex, number of comorbidities, immunosuppression, and SARS-CoV-2 vaccination status was implemented. Results: Data from 428 patients receiving early treatments were collected. The majority were treated with Nirmatrelvir/Ritonavir and were affected by SARS-CoV-2 Omicron infection with BA.2 sublineage. The median length time to SARS-CoV-2 nasal swab negativization was 9 days [IQR 7–13 days]. We found that Nirmatrelvir/Ritonavir determined a significant decrease of the length time to SARS-CoV-2 nasal swab negativization compared to mAbs (p = 0.003), but not compared to Remdesivir (p = 0.147) and Molnupiravir (p = 0.156). Conclusion: Our findings highlight the importance of promptly treating high-risk COVID-19 patients with Nirmatrelvir/Ritonavir, as it also contributes to achieving a faster time to negative SARS-CoV-2 nasal swabs. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses a retrospective study aimed to estimate the prevalence of chronic coinfection with hepatitis B and hepatitis C viruses in a large cohort of HIV-infected persons.

Presents a letter to the editor about the significance of neurologic involvement in patients with sarcoidosis.

Candidemia and invasive candidiasis are major causes of morbidity and mortality, and their incidence is increasing because of the growing complexity of patients. Five species of Candida ( Candida albicans , Candida glabrata , Candida parapsilosis , Candida tropicalis and Candida krusei ) account for more than 90% of all diagnosed cases, but their relative frequency varies depending on the population involved, geographical region, previous anti-fungal exposure, and patient age. The best evidence regarding the anti-fungal treatment for invasive candidiasis comes from randomized controlled trials in which more than 85% of the recruited patients had candidemia. In the case of less frequent forms of invasive candidiasis, the recommendations are based on retrospective studies, meta-analyses (when available) and experts' opinions. A pre-emptive approach based on biomarkers and clinical rules is recommended because of the high rate of infection-related mortality among critically ill patients. [ABSTRACT FROM AUTHOR]

Objectives: Liver transplantation (LTx) is considered a safe procedure in selected HIV-infected patients. In this clinical setting raltegravir is the antiretroviral of choice due to its optimal tolerability and its negligible interactions with immunosuppressive drugs. We aimed at providing data on the pharmacokinetics of raltegravir in LTx recipients, on which the available information is inconclusive.Methods: In this retrospective multicentre study we characterized the pharmacokinetics of raltegravir in a consecutive series of HIV-infected LTx recipients referred to our laboratory for therapeutic drug monitoring (TDM) and compared the obtained profiles with those collected from a control group of HIV-infected patients.Results: Seventeen HIV-infected LTx patients were considered. LTx recipients had significantly higher raltegravir AUC0-12 compared with the control group of HIV-infected patients [14 314 (11 627-19 998) versus 8795 (5218-12 954) ng·h/mL; P < 0.01]. Two LTx patients experienced moderate increments in serum transaminases, nausea and vomiting that improved after raltegravir dose reduction.Conclusions: High raltegravir exposure and acceptable safety profile were observed in HIV-infected LTx recipients. Our results highlight that some patients may obtain an advantage from TDM-guided raltegravir dose adjustments with potential benefits in terms of drug tolerability. [ABSTRACT FROM AUTHOR]

Figure 4 modified: A curves showing survival of participants with severe COVID-19 pneumonia treated with tocilizumab: B. Kaplan-meier survival curves in patients with severe COVID-19 stratified according to ventilation ststus at baseline. B. Incidence of bloodstream infections over the study period. Image, graphical abstract Tocilizumab, a humanized monoclonal antibody, targets IL-6 receptors blocking downstream pro-inflammatory effects of IL-6. In preliminary reports it was suggested to be beneficial in patients with severe COVID-19. In this open-label prospective study we describe clinical characteristics and outcome of 51 patients hospitalized with confirmed and severe COVID-19 pneumonia treated with tocilizumab intravenously. All patients had elevated IL-6 plasma level (>40 pg/mL) and oxygen saturation <93% in ambient air. Clinical outcomes, oxygen support, laboratory data and adverse events were collected over a follow-up of 30 days. Forty-five patients (88%) were on high-flow oxygen supplementation, six of whom with invasive ventilation. From baseline to day 7 after tocilizumab we observed a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count (p <0.001). Over a median follow-up time of 34 days from tocilizumab, 34 patients (67%) showed an improvement in their clinical severity class; 31 were discharged; 17 (33%) showed a worsening of their clinical status, of these 14 died (27%). The mortality rate was significantly associated with mechanical ventilation at baseline (83.3% vs 20% of patients on non-invasive oxygen support; p =0.0001). The most frequent side effects were an increase of hepatic enzymes (29%), thrombocytopenia (14%), and serious bacterial and fungal infections (27%). Tocilizumab exerts a rapidly beneficial effect on fever and inflammatory markers, although no significant impact on the clinical outcome can be inferred by our results. Critically ill patients seem to have a high risk of serious infections with this drug. [ABSTRACT FROM AUTHOR]

Objective: Changes in the incidence, clinical features and microbiology of infective endocarditis (IE) observed in a single center in Italy were compared between the period 2003-2010 and 2011-2015. Methods: All cases of IE, defined as definite or possible according to the modified Duke criteria, observed at the ‘L. Sacco’ Hospital in Milan, Italy between 2003 and 2015 were retrospectively reviewed. Results: 366 episodes of IE were identified in 325 patients. The mean number of incident IE over the period 2003-2015 was 1.43 (range: 0.6-2.1) cases per 1000 admissions, with a significantly increasing trend from a mean of 1.28-1.72 cases per 1000 admissions/year in 2003-2010 and 2011-2015, respectively (+34%; p = .04). Staphylococci remain the leading pathogens causing IE (29%) with a relative increase of methicillin-resistant Staphylococcus aureus between the two periods. Streptococci and enterococci account for 26% and 18% of IE, respectively. We found an increase in the proportion of cases due to enterococci (from 14% in 2003-2010 to 22% in 2011-2015). The rate of in-hospital mortality was 19%, similar in the two periods studied. Conclusion: The incidence of IE continuously increased in our cohort over the past decade and, along with the aging of the population, a raise in the incidence of health care-associated infections and a change in the distribution of prevalent pathogens were observed. Surgery was independently associated with higher in-hospital survival (AOR, 95% CI: 0.38, 0.19-0.74; p = .005). A constant surveillance is required to guide the optimal management of the changing epidemiology of IE. [ABSTRACT FROM AUTHOR]

The renal function is a key-issue in HIV/HCV co-infected patients, nevertheless, it has not established so far whether HCV treatment with new direct acting agents could impact on estimated glomerular filtration rate (eGFR) variations. In the present work, we examined the real-life data on renal function that have been prospectively collected in the SIMIT compassionate-use program of ombitasvir/paritaprevir/ritonavir plus dasabuvir (OBV/PTV/r + DSV) in 144 HIV/HCV genotype 1 co-infected patients. The population was 74% male, 30.5% in CDC stage C, with median age of 52 years (48.0–56.5) and median liver stiffness of 7.8 kPa (6.7–9.2). Median baseline eGFR was 102.0 (90.8–108.1), changing to 99.8 (83.5–104.8) at the end of treatment (EoT), and 100.0 (87.3–105.6) 12 weeks after the EoT (FU12), p<0.0001. No patient had grade 3–4 increase of creatinine. At EoT 60/144 (41.7%) patients had ≥ 5% reduction in their eGFR, confirmed at FU12 in 39/60 (65.0%) cases. Longer duration of HCV infection (cut-off 12.9 years), lower HCV-RNA viral load (cut-off 1,970,160 IU/ml) and lower platelet count (cut-off 167,000 x106/L) were significantly associated with eGFR decline at logistic analysis (adjOR 2.9, 95%CI 1.0–8.8, p = 0.05; adjOR 3.5, 95%CI 1.2–10.4, p = 0.02; adjOR 2.8, 95%CI 1.1–6.8, p = 0.03, respectively). After repeating the analysis throughout a mixed model, a higher eGFR decline was highlighted in patients concomitantly treated with tenofovir (p = 0.0001), ribavirin (p = 0.0001), or integrase inhibitors (p <0.0001), with longer duration of HIV (p = 0.0002) and HCV infection (p = 0.035), lower baseline HCV RNA (p <0.0001), previous HCV treatment (p<0.0001), and older age (p<0.0001). In conclusion, our study confirms a good renal safety profile of OBV/PTV/r + DSV treatment in HIV/HCV patients, and the median decline of 2 ml/min in eGFR, albeit statistically significant, is of doubtful clinical significance. The role of aging, concomitant therapies and duration of HIV/HCV infection needs to be further investigated. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus ( HIV)/hepatitis B virus ( HBV) co-infection is likely to be associated with an increased risk of kidney disease, due to the additional factors that may affect renal function in the HIV population. We aimed to evaluate renal toxicity in HIV/ HBV and HBV mono-infected patients on long-term therapy with tenofovir ( TDF) and to explore the association of polymorphisms in ATP-binding cassette ( ABCC) 2, ABCC4, ABCC10 with the development of renal dysfunction. From September 2006 to November 2014, 44 HIV/ HBV co-infected and 34 HBV mono-infected patients were commenced on TDF. Data of renal safety were retrospectively collected and analyzed. ABCC2, ABCC4 and ABCC10 genotypes were identified by real-time PCR. Over 60 months of observation, there was a significant increase in mean creatinine levels from baseline ( P<.01) that was not significantly different between the two study groups. Moreover, a significant decline in estimated glomerular filtration rate ( eGFR) was observed from baseline ( P<.01), and it was significantly greater in HBV mono-infected than co-infected patients ( P=.03). The distribution of ABCC2, ABCC4 and ABCC10 genotypes among a subgroup of 34 patients did not show significant association with eGFR decline <90 mL/min per 1.73 m2. Although our findings showed a statistically significant decrease in eGFR with long-term use of TDF, its clinical impact seems to be modest. The role of genetic factors to identify patients at greater risk for developing tenofovir-induced renal toxicity needs to be further investigated. [ABSTRACT FROM AUTHOR]

Abstract: Mixed cryoglobulinaemia syndrome (MCS) is associated with a number of infectious, autoimmune and lymphoproliferative disorders, particularly chronic hepatitis C infection. Although circulating mixed cryoglobulins (cMCGs) are a frequent finding in HCV-infected patients, only a minority of them develop a frank MCS. The only available data concerning the prevalence of MCS, which is generally considered a rare disease, come from hospital records. The aim of this investigation was to estimate the prevalence of cMCGs and MCS in a population-based study. All of the adult residents in Origgio, a town of about seven thousand inhabitants in northern Italy, were mailed a validated questionnaire, and a randomly selected sample of respondents was invited to undergo a clinical examination and laboratory tests including the determination of cMCGs. The 1594 respondents to the questionnaire (54.3% women, 64.5% aged >49years) accounted for 26.4% of the total adult population. Forty-nine (3.1%) positively responded to at least two questions, including a disproportionately high number of people aged >70years (p=0.001). Of the 266 randomly selected subjects invited to undergo a clinical examination and laboratory tests, 147 accepted, 30 (20.4%) of whom had asymptomatic type III cMCGs and four MCS. The risk of cMCG positivity was independently associated with C4 levels of <16mg/dL (adjusted odds ratio [AOR] 4.40, 95% confidence interval [CI] 1.07–18.08; p=0.040) and HCV positivity (AOR 6.87, 95% CI 1.16–40.79; p=0.034). No co-morbidities known to be related to cMCG production could be detected in more than 50% of the positive cases. After including the other positive respondents who agreed to undergo a clinical examination, the number of diagnosed MCS increased to seven: five HCV-related, one HBV-related, and one essential MCS. In conclusion, MCS seems to be more frequent than expected for a ‘rare’ disease, and the unexpectedly high prevalence of cMCGs raises questions about the frequency with which they are triggered, the spectrum of diseases involved in triggering them, and their real role as disease indicators. [Copyright &y& Elsevier]

Abstract: Objective: The objective of this review was to define a core set of recommendations for the treatment of HCV-associated mixed cryoglobulinemia syndrome (MCS) by combining current evidence from clinical trials and expert opinion. Methods: Expert physicians involved in studying and treating patients with MCS formulated statements after discussing the published data. Their attitudes to treatment approaches (particularly those insufficiently supported by published data) were collected before the consensus conference by means of a questionnaire, and were considered when formulating the statements. Results: An attempt at viral eradication using pegylated interferon plus ribavirin should be considered the first-line therapeutic option in patients with mild–moderate HCV-related MCS. Prolonged treatment (up to 72weeks) may be considered in the case of virological non-responders showing clinical and laboratory improvements. Rituximab (RTX) should be considered in patients with severe vasculitis and/or skin ulcers, peripheral neuropathy or glomerulonephritis. High-dose pulsed glucocorticoid (GC) therapy is useful in severe conditions and, when necessary, can be considered in combination with RTX; on the contrary, the majority of conference participants discouraged the chronic use of low–medium GC doses. Apheresis remains the elective treatment for severe, life-threatening hyper-viscosity syndrome; its use should be limited to patients who do not respond to (or who are ineligible for) other treatments, and emergency situations. Cyclophosphamide can be considered in combination with apheresis, but the data supporting its use are scarce. Despite the limited available data, colchicine is used by many of the conference participants, particularly in patients with mild–moderate MCS refractory to other therapies. Careful monitoring of the side effects of each drug, and its effects on HCV replication and liver function tests is essential. A low-antigen-content diet can be considered as supportive treatment in all symptomatic MCS patients. Although there are no data from controlled trials, controlling pain should always be attempted by tailoring the treatment to individual patients on the basis of the guidelines used in other vasculitides. Conclusion: Although there are few controlled randomised trials of MCS treatment, increasing knowledge of its pathogenesis is opening up new frontiers. The recommendations provided may be useful as provisional guidelines for the management of MCS. [Copyright &y& Elsevier]

We describe a case of disseminated Penicillium marneffei in a human immunodeficiency virus (HIV)–positive Italian man who stayed for 4 years in Chiang Ray province, northern Thailand. A review of the literature shows that penicilliosis, although unusual, may represent an emerging opportunistic infection among HIV-positive people traveling to endemic areas. [ABSTRACT FROM AUTHOR]