Nocardia Infections in the Immunocompromised Host: A Case Series and Literature Review.

Nocardia is primarily considered an opportunistic pathogen and affects patients with impaired immune systems, solid-organ transplant recipients (SOTRs), and patients with haematologic malignancies. We present the cases of six patients diagnosed with nocardiosis at our center in the last two years, describing the various predisposing conditions alongside the clinical manifestation, the diagnostic workup, and the treatment course. Moreover, we propose a brief literature review on Nocardia infections in the immunocompromised host, focusing on SOTRs and haematopoietic stem cell transplantation recipients and highlighting risk factors, clinical presentations, the diagnostic tools available, and current treatment and prophylaxis guidelines.

Pneumocystis jirovecii pneumonia in HIV-negative patients, a frequently overlooked problem. A case series from a large Italian center.

BACKGROUND AND OBJECTIVES: Pneumocystis jirovecii pneumonia (PCP) still has substantial morbidity and mortality. For non-HIV patients, the course of infection is severe, and management guidelines are relatively recent. We collected all PCP cases (European Organization for Research and Treatment of Cancer criteria) diagnosed in HIV-negative adult inpatients in 2019-2020 at our center in northern Italy. RESULTS: Of 20 cases, nine had microbiologic evidence of probable (real-time polymerase chain reaction, RT-PCR) and 11 proven (immunofluorescence) PCP on respiratory specimens. Half were female; the median age was 71.5 years; 14 of 20 patients had hematologic malignancies, five had autoimmune/hyperinflammatory disorders, and one had a solid tumor. RT-PCR cycle threshold (Ct) was 24-37 for bronchoalveolar lavage (BAL) and 32-39 for sputum; Ct was 24-33 on BAL proven cases. Of 20 cases, four received additional diagnoses on BAL. At PCP diagnosis, all patients were not on anti-pneumocystis prophylaxis. We retrospectively assessed prophylaxis indications: 9/20 patients had a main indication, 5/9 because of prednisone treatment ≥ 20 mg (or equivalents) for ≥4 weeks. All patients underwent antimicrobial treatment according to guidelines; 18/20 with concomitant corticosteroids. A total of 4/20 patients died within 28 days from diagnosis. CONCLUSION: Despite appropriate treatment, PCP is still associated to high mortality (20%) among non-HIV patients. Strict adherence to prophylaxis guidelines, awareness of gray areas, and prompt diagnosis can help manage this frequently overlooked infection.

Infectious events in patients treated with immune checkpoint inhibitors, chimeric antigen receptor T cells, and bispecific T-cell engagers: a review of registration studies.

BACKGROUND: Immunological treatments (immune checkpoint inhibitors [ICIs], chimeric antigen receptor T [CAR-T] cells, bispecific T-cell engagers [BiTEs]) have deeply changed the treatment of several cancers. However, the impact of these treatments on the risk of developing infections has not been completely ascertained yet. METHODS: We reviewed all the registration studies of currently approved ICIs, CAR-T cells, and BiTEs to collect all the reported infections. For each drug, we have generated a report with the infections occurring in at least 10% of the patients enrolled. RESULTS: The most frequently reported infections involving patients treated with ICIs involved the respiratory tract, including nasopharyngitis, upper respiratory tract infections, and pneumonia and the urinary tract. Those treated with CAR-T cells frequently reported the incidence of unspecified infections and infestations, bacterial infections, and viral infections. In patients treated with BiTEs, nasopharyngitis, pneumonia, and device-related infections were the most frequently reported conditions. CONCLUSIONS: A wide range of infections are reported in registration studies and clinical trials of ICIs, CAR-T cells, and BiTEs.

Immune Checkpoint Inhibitors in People Living with HIV/AIDS: Facts and Controversies.

Immune checkpoint inhibitors (ICIs) are reshaping the landscape of cancer treatment, redefining the prognosis of several tumors. They act by restoring the cytotoxic activity of tumor-specific T lymphocytes that are in a condition of immune exhaustion. The same condition has been widely described in chronic HIV infection. In this review, we dissect the role of ICIs in people living with HIV/AIDS (PLWHIV). First, we provide an overview of the immunologic scenario. Second, we discuss the possible use of ICIs as adjuvant treatment of HIV to achieve elimination of the viral reservoir. Third, we examine the influence of HIV infection on ICI safety and effectiveness. Finally, we describe how the administration of ICIs impacts opportunistic infections.

HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression?

The prevalence of the most severe forms of HIV-associated neurocognitive disorders (HAND) is decreasing due to worldwide availability and high efficacy of antiretroviral treatment (ART). However, several grades of HIV-related cognitive impairment persist with effective ART and remain a clinical concern for people with HIV (PWH). The pathogenesis of these cognitive impairments has yet to be fully understood and probably multifactorial. In PWH with undetectable peripheral HIV-RNA, the presence of viral escapes in cerebrospinal fluid (CSF) might explain a proportion of cases, but not all. Many other mechanisms have been hypothesized to be involved in disease progression, in order to identify possible therapeutic targets. As potential indicators of disease staging and progression, numerous biomarkers have been used to characterize and implicate chronic inflammation in the pathogenesis of neuronal injuries, such as certain phenotypes of activated monocytes/macrophages, in the context of persistent immune activation. Despite none of them being disease-specific, the correlation of several CSF cellular biomarkers to HIV-induced neuronal damage has been investigated. Furthermore, recent studies have been evaluating specific microRNA (miRNA) profiles in the CSF of PWH with neurocognitive impairment (NCI). The aim of the present study is to review the body of evidence on different biomarkers use in research and clinical settings, focusing on PWH on ART with undetectable plasma HIV-RNA.

Nonalcoholic fatty liver disease and steatohepatitis in people living with HIV.

Introduction: The burden of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing worldwide. This phenomenon poses a potentially dangerous risk of rise in mortalities caused by cirrhosis and liver cancer. Owing to a complex combination of factors, NAFLD and NASH arise in a majority of people living with HIV (PLWH), but accurate estimates of prevalence differ, depending on sample selection, type of analysis, and data interpretation. The wide range of diagnostic tools used to assess liver steatosis and lack of control groups in many studies further contributes to current difficulties in properly assessing prevalence of these conditions. Areas covered: Thoroughly scrutinizing the current literature, we compared the prevalence of NAFLD and NASH in PLWH to rates found in the general population. We highlighted strengths and limitations of the studies, in order to determine the effective impact of these medical conditions in PLWH. Expert opinion: The prevalence and progression of NAFLD in human immunodeficiency virus (HIV) infection are reported to be widely variable. HIV infection itself and antiretroviral treatment have been demonstrated to play a role in the development of NAFLD. Larger and more effective studies are needed to evaluate the effects of NASH in PLWH and its progression.

Darunavir-cobicistat-emtricitabine-tenofovir alafenamide: safety and efficacy of a protease inhibitor in the modern era.

A fixed-dose combination consisting of darunavir (Drv), cobicistat (Cobi), emtricitabine (2',3'-dideoxy-5-fluoro-3'-thiacytidine [FTC]), and tenofovir alafenamide (Taf) has been recently approved by the European Medicines Agency for the treatment of HIV infection, and is the first ever protease-inhibitor-based single-tablet regimen. This article provides a detailed description of its pharmacokinetic, efficacy, and safety profile. The pharmacokinetics of single compounds were analyzed, with a special focus on contrasts between Drv/Cobi and Drv/ritonavir (Rtv). When comparing Cobi and Rtv, multiple interactions must be taken into account: in comparison to Rtv, Cobi is a more selective CYP3A4 inhibitor and has no clinical effect on other isoenzymes inhibited by Rtv (eg, 2C8 and 2C9). Moreover, unlike Cobi, Rtv shows in vivo induction activity on some CYP isoenzymes (eg, 1A2, 2C19, 2C8, 2C9, and 2B6), glucuronyltransferases (eg, UGT1A4), and Pgp. Drv-Cobi-FTC-Taf has recently been demonstrated to be of equal efficacy to Drv-Rtv and other protease inhibitors in both experienced (EMERALD study) and naïve (AMBER study) patients. Moreover, kidney and bone safety profiles have been shown to be good, as has central nervous system tolerance. Total cholesterol:low-density-lipoprotein cholesterol and total cholesterol:high-density-lipoprotein cholesterol ratios are generally high in Drv-Cobi-FTC-Taf vs Rtv-Drv-FTC + tenofovir disoproxil fumarate. An unlikely role of Drv in influencing cardiovascular risk in HIV infection has also been reported. Kidney safety profile is influenced by Cobi, with an increase in creatinine plasma concentration of 0.05-0.1 mg/dL and a parallel glomerular filtration-rate reduction of 10 mL/min within the first 4 weeks after Cobi introduction, which remains stable during treatment. Bone and central nervous system safety profiles were found to be good in randomized clinical trials of both experienced and naïve patients. The efficacy and safety of Drv/Cobi/FTC/Taf are comparable to other drug regimens recommended for HIV treatment.