Caspofungin for primary antifungal prophylaxis after T-cell-replete haploidentical stem cell transplantation with post-transplant cyclophosphamide.

OBJECTIVES: T-cell-replete haploidentical stem cell transplantation (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is at high risk of invasive fungal infections (IFI), and anti-mold-active drug is required for primary antifungal prophylaxis (PAP) according to international guidelines. No data are available on the efficacy of caspofungin as PAP in this setting. METHODS: Here, we report our retrospective experience with 103 consecutive patients treated with caspofungin as PAP after Haplo-SCT. Caspofungin was administered only during the pre-engraftment phase. RESULTS: Hundred-day cumulative incidence of proven-probable IFI (PP-IFI) was 8.7% and median day of onset was 19 post-SCT. No patient died of PP-IFI, and overall survival (OS) and non-relapse mortality (NRM) hazard ratio (HR) for patients experiencing IFI were 1.02 (P = 0.9) and 0.7 (P = 0.7), respectively. Three-year overall survival (OS) and 1-year non-relapse mortality (NRM) were 55% and 19%, respectively. By univariate analysis, duration of neutropenic phase and partial remission pre-transplant disease status were associated with increased incidence of IFI, but were not confirmed by multivariate analysis. CONCLUSION: In summary, PAP with caspofungin is an effective strategy for preventing IFI in the context of Haplo-SCT with PT-Cy. Further efforts are required in order to identify more potent strategies able to avoid the occurrence of breakthrough infections.

A reduced dose of fluconazole as primary antifungal prophylaxis is not associated with increased risk of invasive fungal infections after allogeneic stem cell transplantation from a HLA identical sibling.

BACKGROUND: Invasive fungal infections (IFI) represent a common side effect of allogeneic hematopoietic stem cell transplant (allo-SCT), resulting in increased non relapse mortality (NRM) and reduced overall survival (OS) rates. Seventy-five days of Fluconazole 400 mg/d represents the standard primary antifungal prophylaxis (PAP) after allo-SCT, especially for low-risk transplants. However, the ideal dosage of fluconazole has never been tested. METHODS: Here, we report the experience of our institution on 113 consecutive patients receiving an allo-SCT from a HLA identical sibling between 1999 and 2015, where PAP consisted of fluconazole 100 mg/d only during the pre-engraftment phase. At the time of transplant, all patients were considered at low-risk for mold infection according to ECIL-5 guidelines. RESULTS: Cumulative incidence of possible-probable-proven IFI was 11.7%, while proven-probable (PP-IFI) occurred in 5.5% of patients by day 100 post transplant. Of note, only 1 patient developed invasive Candidiasis due to a non-albicans strain and stool-screening tests were negative for colonization by Candida albicans species. The incidence of 1-year acute and 2-year chronic graft-versus-host-disease (GVHD) was 30% and 45%, respectively. Three-year OS and 1-year NRM were 53% and 11.3%, respectively. CONCLUSION: In summary, fungal prophylaxis with fluconazole 100 mg/d results in very low incidence of PP-IFI, GVHD and NRM in low-risk allo-SCT.

Quantitative Chest CT Analysis to Measure Short-Term Sequelae of COVID-19 Pneumonia: A Monocentric Prospective Study.

(1) Background: Quantitative CT analysis (QCT) has demonstrated promising results in the prognosis prediction of patients affected by COVID-19. We implemented QCT not only at diagnosis but also at short-term follow-up, pairing it with a clinical examination in search of a correlation between residual respiratory symptoms and abnormal QCT results. (2) Methods: In this prospective monocentric trial performed during the "first wave" of the Italian pandemic, i.e., from March to May 2020, we aimed to test the relationship between %deltaCL (variation of %CL-compromised lung volume) and variations of symptoms-dyspnea, cough and chest pain-at follow-up clinical assessment after hospitalization. (3) Results: 282 patients (95 females, 34%) with a median age of 60 years (IQR, 51-69) were included. We reported a correlation between changing lung abnormalities measured by QCT, and residual symptoms at short-term follow up after COVID-19 pneumonia. Independently from age, a low percentage of surviving patients (1-4%) may present residual respiratory symptoms at approximately two months after discharge. QCT was able to quantify the extent of residual lung damage underlying such symptoms, as the reduction of both %PAL (poorly aerated lung) and %CL volumes was correlated to their disappearance. (4) Conclusions QCT may be used as an objective metric for the measurement of COVID-19 sequelae.

Assessing the impact of hepatitis C virus coinfection on lopinavir/ritonavir trough concentrations in HIV-infected patients.

PURPOSE: Chronic hepatitis C is an emerging issue in the management of human immunodeficiency virus (HIV) disease because both diseases have the same route of transmission, leading to a very high prevalence of hepatitis C virus (HCV)-coinfection in the HIV-positive patient population. Lopinavir is extensively metabolized by the hepatic cytochrome P450 3A4, and the pharmacokinetics of this protease inhibitor (PI) could be influenced by liver impairment. However, data currently available on the impact of HCV-coinfection on lopinavir plasma concentrations are both limited and conflicting. METHODS: This was an observational, open-label study in which adult HIV-infected outpatients on stable antiretroviral treatment that included two nucleoside reverse transcriptase inhibitors (NRTIs) plus lopinavir/ritonavir for at least 4 weeks were asked to participate. The trough plasma concentration (C (trough)) of lopinavir and ritonavir was assessed at steady state by a validated high-performance liquid chromatography-tandem mass spectrometry method. RESULTS: A total of 65 HIV-positive patients were enrolled in the study. These patients were stratified into two groups based on the absence/presence of HCV-coinfection: 45 were monoinfected (HIV+/HCV-) and 20 were coinfected (HIV+/HCV+). The lopinavir C (trough) in plasma was comparable between HIV+/HCV+ and HIV+/HCV- patients, without any statistically significant difference (geometric mean ratio 0.89, 95% confidence interval 0.61-1.42; p = 0.581). The mean ritonavir C (trough) was also comparable in the two groups. Almost all samples were found to be within the therapeutic plasma level range (97% in HIV+/HCV- group and 100% in HIV+/HCV+ group). No correlation was found between lopinavir plasma levels and adverse events (such as diarrhoea and hypertriglyceridaemia) or immune-virological parameters of HIV disease. CONCLUSIONS: Among the HIV-positive patients participating in this study, the pharmacokinetics of lopinavir/ritonavir did not significantly change in those HIV-positive patients coinfected with HCV and in the absence of liver cirrhosis.

The Use of Antiviral Agents against SARS-CoV-2: Ineffective or Time and Age Dependent Result? A Retrospective, Observational Study among COVID-19 Older Adults.

BACKGROUND: Our aim was to investigate the impact of therapeutics with antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on mortality of older adults affected by coronavirus disease 2019 (COVID-19), taking into consideration the time interval from symptoms onset to drugs administration. METHODS: Data from 143 COVID-19 patients over 65 years of age admitted to the Humanitas Clinical and Research Center Emergency Department (Milan, Italy) and treated with Lopinavir/ritonavir (LPV/r) or Darunavir/cobicistat (DVR/c) associated to Hydroxychloroquine (HCQ) were retrospectively analyzed. Statistical analysis was performed by using a logistic regression model and survival analysis to assess the role of different predictors of in-hospital mortality, including an early (<6 days from symptoms onset) vs. late treatment onset, signs and symptoms at COVID-19 presentation, type of antiviral treatment (LPV/r or DVR/c) and patients' age (65-80 vs. >80 years old). RESULTS: Multivariate analysis showed that an older age (OR: 2.54) and dyspnea as presenting symptom (OR: 2.01) were associated with higher mortality rate, whereas cough as presenting symptom (OR: 0.53) and a timely drug administration (OR: 0.44) were associated with lower mortality. Survival analysis demonstrated that the timing of drug administration had an impact on mortality in 65-80 years-old patients (p = 0.02), whereas no difference was seen in those >80 years-old. This impact was more evident in patients with dyspnea as primary symptom of COVID-19, in whom mortality decreased from 57.1% to 38.3% due to timely drug administration (OR: 0.5; p = 0.04). CONCLUSIONS: There was a significant association between the use of a combined antiviral regimen and HCQ and lower mortality, when timely-administered, in COVID-19 patients aged 65-80 years. Our findings support timely treatment onset as a key component in the treatment of COVID-19.

Anti-inflammatory effect of maraviroc in an HIV-infected patient with concomitant myositis: a case report.

We report the surprising yet sought impact that an antiretroviral (ARV) regimen containing maraviroc had on an HIV-infected and heavily highly active antiretroviral therapy (HAART)-experienced patient with chronic polymyositis. The patient had elevated creatine kinase (CK) levels in serum for 6 years, reaching peaks over 900 U/L and showing only partial response to high-dose steroids, not responding to HAART withdrawal. The disease started while on second-line HAART and gradually impaired his muscular function, leading to the absolute loss of the ability to stand on his legs. Atherosclerosis and hypertension contributed to the development of myocardial infarction. The association of unboosted atazanavir (ATV) plus maraviroc was designed hoping in a protective role on the cardiovascular system and in an anti-inflammatory effect that some authors have hypothesized. After only 3 months the patient's CK levels had normalized and with the help of rehabilitation he recovered the ability to walk, which he still maintains at the one year of observation.

Efficacy of intraventricular amikacin treatment in pan-resistant Pseudomonas aeruginosa postsurgical meningitis.

BACKGROUND: We describe a case of pan-resistant Pseudomonas aeruginosa postsurgical meningitis associated with the presence of an external ventricular device. We changed therapy twice; finally, by using amikacin and a continuous infusion of cefepime, we obtained clinical improvement. CASE PRESENTATION: A female patient, who underwent surgery for a cavernous angioma, presented with meningitis. Cerebrospinal fluid culture revealed a multidrug-resistant Pseudomonas aeruginosa, initially sensitive only to colistin. We successfully used intrathecal amikacin and intravenous cefepime continuous infusion plus intravenous amikacin after two previous ineffective therapeutic approaches. CONCLUSION: The evaluation of the antibiotic concentration and the bactericidal activity in cerebrospinal fluid may contribute to the choice of the drug in cases of multidrug-resistant meningitis.

Maraviroc Reduces Arterial Stiffness in PI-Treated HIV-infected Patients.

The Δ32-CCR5 deletion of the CCR5 receptor is protective toward coronary artery pathology and myocardial infarction. Maraviroc (MVC), a CCR5 antagonist, was recently introduced in the therapy of HIV infection; we evaluated whether this drug could modulate the atherosclerotic burden in aviremic PI-treated HIV-positive individuals who underwent MVC intensification. Thus, the effect of MVC on intima media thickness, arterial stiffness, metabolic parameters, pro-inflammatory cytokines, endothelial dysfunction, and microbial traslocation markers was analyzed in 6 aviremic PI-treated HIV-positive individuals and were compared to those obtained in 9 additional aviremic PI-treated subjects that were enrolled retrospectively from our outpatients cohort. MVC intensification resulted in a significant reduction in intima media thickness, pulse wave velocity and triglycerides compared to baseline. Notably, MVC was also associated with a significant reduction of IL-6, microbial translocation indexes, sICAM and sVCAM; these changes were maintained throughout the 6 months of MVC intensification. No significant modifications were observed in CD4 counts, HIV viral load, and cholesterolemia. Results herein support a role of CCR5 antagonists in reducing the cardiovascular risk in HIV-infection. The hampering of inflammation, microbial translocation and the improvement of endothelial function could justify the protective role of CCR5 antagonists on atherosclerotic burden.

Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia.

OBJECTIVES: To evaluate simplified protease inhibitor (PI)-sparing antiretroviral treatment versus lipid-lowering therapy for the management of highly active antiretroviral therapy (HAART)-induced hyperlipidaemia. DESIGN: Randomized, open-label clinical trial assessing the efficacy on hyperlipidaemia of a switching therapy from PI to non-nucleoside reverse transcriptase inhibitor (NNRTI) nevirapine or efavirenz versus a hypolipidaemic treatment (with pravastatin or bezafibrate) added to current, unchanged antiretroviral combination. METHODS: All HIV-infected patients on their first HAART regimen, with stable immuno-virological features, naive to all NNRTIs, and with mixed hyperlipidaemia, were randomized to replace PI with nevirapine (arm A) or efavirenz (arm B), or to receive pravastatin (arm C) or bezafibrate (arm D) with unchanged HAART regimen, and were followed-up for 12 months. RESULTS: One hundred and thirty patients were evaluated: 29 patients were randomized to arm A, 34 to arm B, 36 to arm C, and 31 to arm D. At the end of the 12-month follow-up, a reduction of 25.2, 9.4, 41.2 and 46.6% in mean triglyceridaemia versus respective baseline values was reported in groups A, B, C and D, respectively, with statistically significant difference between arms A-B and C-D (P < 0.01). Similar results were reported for total and low-density lipoprotein cholesterol levels. Viro-immunological efficacy and tolerability profile were comparable in all considered arms. CONCLUSION: Pravastatin and bezafibrate proved significantly more effective in the management of HAART-related hyperlipidaemia than the switching therapy from PI to nevirapine or efavirenz.

Rosuvastatin for the treatment of hyperlipidaemia in HIV-infected patients receiving protease inhibitors: a pilot study.

Sixteen HIV-infected patients with protease inhibitor (PI)-related, persisting hypercholesterolaemia were treated with 10 mg a day rosuvastatin for 24 weeks. At the end of the observation period, the median reductions in total cholesterol and triglyceride levels versus median baseline values were 21.7 and 30.1%, respectively (P < 0.01). In our small pilot study, rosuvastatin was found to be effective for the treatment of PI-associated hyperlipidaemia, in association with a favourable tolerability profile, without significant clinical or laboratory adverse events.

The feature of Metabolic Syndrome in HIV naive patients is not the same of those treated: results from a prospective study.

Metabolic Syndrome (MS) is a common disorder combining obesity, dyslipidemia, hypertension, and insulin resistance. Its prevalence among HIV-infected people is still debated. Besides, how antiretroviral therapy and HIV infection per se are related to MS is still unclear. All treatment-naïve patients attending scheduled visits at CISAI group hospitals between January and December 2007 were eligible for the study. Patients without MS at enrolment were followed-up for 3 years or until they developed MS, diagnosed according to the National Cholesterol Education Program (NCEP) definition. The main objective was to assess the 3-years incidence of MS. MS was evaluated for 188 subjects. Out of them, 62 (33.0%) had started HAART at enrolment, whereas 67 (35.6%) more started during the observation. 59 (31.4%) were still treatment-naive at the study end. MS was newly diagnosed in 14 patients. The incidence was 2.60 cases/100 person-years (95% CI 1.47-4.51), 2.75 (1.11-5.72) among HAART-naïve patients and 2.65 (1.23-5.03) in subjects on HAART. Blood pressure did not change in the study period, whereas in naive patients the HDL level significantly lowered (median -6.0 vs. 4.0, P<0.0001) compared to HAART-treated patients. Triglicerides increased significantly in HAART subjects (median 12.0 vs. 1.0, P=0.02), as well as blood glucose (median 6.0 vs. 1.0, P=0.01). In our population, the overall MS incidence was low and largely similar in patients who started HAART or remained naive. However, the feature of MS was different in the two groups, suggesting that in untreated and treated patients MS developed through different metabolic pathways.

The burden of metabolic diseases amongst HIV positive patients on HAART attending The Johannesburg Hospital.

South Africa has the highest prevalence of human immunodeficiency virus (HIV) infection in the world. The improved life expectancy, due to the recent introduction of highly active antiretroviral therapy (HAART), may lead to an increased health burden related to metabolic disorders, resulting in an increased pressure on health-care services. The main objective of this study was to determine the prevalence of hypertension, diabetes, obesity and dyslipidemia in a sample of HAART-treated HIV infected patients, attending an HIV clinic in the Gauteng province. This was a cross-sectional study of 304 HIV positive patients enrolled between January 2009 and March 2009, including patients aged 18 to 45 years, on HAART for more than one year. Hypertension prevalence was 19.1% (95% confidence interval (CI) 14.7-23.5): 23.9% in men and 17.7% in women (P=0.10). Diabetes was diagnosed in 4 women. Hypercholesterolemia (total cholesterol >5.00 mmol/mL) was found in 32.2% (95% CI 27.0-37.5), low HDL cholesterol (<1.20 mmol/mL) in 45.7% (95% CI 40.1-51.3) and elevated LDL cholesterol (>4.10 mmol/mL) in 9.5% (95% CI 6.2-12.8); these prevalences were not different between sexes, whereas hypertriglyceridemia (>2.25 mmol(mL) (15.8%, 95% CI 11.7-19.9) was significantly more frequent in men (28.4% versus 12.2%, P=0.002). TC and LDL-C were positively correlated with CD4+ cell count (r=0.13, P=0.03 and r=0.12, P=0.03). In this sample, the traditional risk factors for cardiovascular disease had a high prevalence, despite the young age of our patients. Women seemed to be at higher risk than man, unlike other HIV populations where these comparisons were made (Uganda, Italy and Norway). Obesity and lipid abnormalities, highly prevalent in the general population, also appeared related to HIV-infection and CD4+ cell count, presumably as a consequence of ART exposure. Further studies are needed in order to survey a population where HIV infection is turning into a chronic disease, with its complications.

Secondary hyperparathyroidism in HIV patients: is there any responsibility of highly active antiretroviral therapy?

Secondary hyperparathyroidism may develop in the presence of hypovitaminosis D in order to maintain calcium homeostasis. We conducted a cross-sectional analysis in a cohort of 371 patients, identifying secondary hyperparathyroidism in 65 patients. This high prevalence (17.5%) was in part justified by the high prevalence of hypovitaminosis D (77.4%) in the whole sample, but we also identified an independent association with the use of tenofovir.

Efficacy and safety of atazanavir-ritonavir plus abacavir-lamivudine or tenofovir-emtricitabine in patients with hyperlipidaemia switched from a stable protease inhibitor-based regimen including one thymidine analogue.

Randomized, open-label, prospective clinical trial assessing efficacy and safety on hyperlipidemia of a switching from a regimen including one protease inhibitor and one thymidine analogue to atazanavir/ritonavir plus abacavir/lamivudine or tenofovir/emtricitabine. Adult HIV-infected patients on their first antiretroviral therapy (of at least 48-week duration), including one protease inhibitor and zidovudine or stavudine, with stable immunovirologic features, and having diagnosis of persisting hyperlipidemia, were randomized to replace current treatment with atazanavir/ritonavir plus abacavir/lamivudine (arm A) or tenofovir/emtricitabine (arm B), and were followed for 48 weeks. Eighty-nine patients were enrolled: 42 patients were randomized to arm A, and 47 to arm B. At the end of the 48-week follow-up, incidence of virologic failure was comparable in both arms, and associated with a poor drug compliance. Increase in CD4 lymphocyte count was significantly higher in arm A after a 24-week study period (62.5 versus 39.2 x 10(6) cells/L; p < 0.05), while immunologic responses were comparable at the end of 48-week follow-up (91.5 versus 83.6; p > 0.05). A statistically significant reduction (-15.4%) in mean triglyceridaemia versus respective baseline values was reported in both groups (p < 0.05), without statistically significant difference between arm A and B. Similar results were reported for total cholesterol and low-density lipoprotein (LDL) cholesterol levels. Safety and tolerability profiles were comparable in both groups. Switching from a protease inhibitor- and thymidine analogue-based antiretroviral regimen to atazanavir/ritonavir plus abacavir/lamivudine or tenofovir/emtricitabine proved effective in the management of hyperlipidemia, without significant differences in lipid-lowering effect, virologic efficacy, and safety profile between these regimens.

Risk of premature atherosclerosis and ischemic heart disease associated with HIV infection and antiretroviral therapy.

The use of new potent protease inhibitor-based antiretroviral therapies in patients with human immunodeficiency virus (HIV) infection has been increasingly associated with cardiovascular risk factors, including hyperlipidaemia, fat redistribution syndrome, insulin resistance, and diabetes mellitus. The introduction of highly active antiretroviral therapy (HAART) in clinical practice has remarkably changed the natural history of HIV disease, leading to a notable extension of life expectancy, and prolonged lipid and glucose metabolism abnormalities are expected to lead to significant effects on the long-term prognosis and outcome of HIV-infected patients. Prediction modeling, surrogate markers and hard cardiovascular endpoints suggest an increased incidence of cardiovascular diseases in HIV-infected subjects receiving HAART, even though the absolute risk of cardiovascular complications remains still low, and must be balanced against the evident virological, immunological, and clinical benefits descending from combination antiretroviral therapy. Nevertheless, the assessment of cardiovascular risk should be performed on regular basis in HIV-positive individuals, especially after initiation or change of antiretroviral treatment. Appropriate lifestyle measures (including smoking cessation, dietary changes, and aerobic physical activity) are critical points, and switching HAART may be considered, although maintaining viremic control should be the main goal of therapy. Pharmacological treatment of dyslipidaemia (usually with statins and fibrates), and hyperglycaemia (with insulin-sensitizing agents and thiazolidinediones), becomes suitable when lifestyle modifications and switching therapy are ineffective or not applicable.

Rosuvastatin, pravastatin, and atorvastatin for the treatment of hypercholesterolaemia in HIV-infected patients receiving protease inhibitors.

Highly active antiretroviral therapy (HAART) including protease inhibitors (PIs) has been independently associated with an abnormal lipid profile, and recent studies have shown an increased risk of cardiovascular complications in patients with prolonged exposure to HAART. Aim of our open-label, randomized, prospective study is to evaluate the role of different statins in the management of PI-associated hypercholesterolaemia. Ninety-four adult patients on a stable PI-based antiretroviral therapy since at least 12 months, and presenting hypercholesterolaemia (total cholesterol level >250 mg/dL) of at least 3-month duration and unresponsive to a hypolipidaemic diet and physical exercise, were randomized to a hypolipidaemic treatment with rosuvastatin (10 mg once daily), pravastatin (20 mg once daily) or atorvastatin (10 mg once daily), and were followed-up for 12 months. Among the 85 subjects who completed the study, rosuvastatin was employed in 26 cases, pravastatin in 31, and atorvastatin in 28. At the close of 1-year follow-up, statins led to a mean reduction of 21.2% and 23.6% versus baseline total cholesterol and LDL cholesterol levels, respectively (p=0.002). Mean decrease in total cholesterol concentration was significantly greater with rosuvastatin (25.2%) than with pravastatin (17.6%; p=0.01) and atorvastatin (19.8%; p=0.03). During these 12 months, all administered statins showed a favourable tolerability profile, and patients' plasma HIV viral load did not present any variation. All used statins showed a significant efficacy and a good tolerability in the treatment of diet-resistant hyperlipidaemia, but rosuvastatin was found to be more effective in reducing total and LDL cholesterol levels.