Personalized care approaches to hepatitis C therapy: recent advances and future directions.

INTRODUCTION: The introduction of direct-acting antivirals (DAAs) has significantly transformed the therapeutic landscape for chronic C hepatitis virus (HCV) infection. However, there is still room for further improvement in optimizing therapy efficacy and minimizing adverse effects. AREAS COVERED: This review is devoted to the rationale for adopting a personalized approach to HCV therapy. Specifically, we explore the role of host-related factors, such as sex or the presence of comorbidities. We thoroughly examine the implications of commonly encountered comorbidities, including HIV infection, chronic renal disease, liver cirrhosis, and other chronic viral hepatitis infections. Additionally, we discuss the prevalent drug-to-drug interactions between DAAs and other medications, while providing guidance on their management. Finally, we investigate viral-related issues that can influence treatment outcomes, such as viral genotype, quasi-species, and the presence of resistance-associated mutations. EXPERT OPINION: Despite pivotal trials demonstrating efficacy rates exceeding 90% for currently available DAA regimens, there are still opportunities to optimize therapy outcomes and tailor treatment to each patient. This can be achieved through a meticulous evaluation of the patient's specific clinical conditions and comorbidities, a vigilant approach to manage potential drug interactions, and diligent patient follow-up.

Impact of oral antiviral therapy against HCV on gut microbiota. A prospective study.

The intestinal microbiota plays a fundamental role in physiological homeostasis as well as in pathologic conditions. Hepatitis C virus is the leading cause of chronic liver diseases worldwide. The treatment of this infection has been revolutionized by the availability of direct-acting antiviral agents which guarantee a high rate (about 95%) of viral clearance. Few studies have assessed the change in the gut microbiota of patients treated with direct-acting antiviral agents against HCV, and many aspects still need to be clarified. The aim of the study was to evaluate the effects of antiviral therapy on gut microbiota. We enrolled patients with HCV-related chronic liver disease attending the Infectious Diseases Unit of the A.O.U. Federico II of Naples from January 2017 to March 2018 and treated with DAAs. For each patient, a fecal sample was collected and analyzed for the assessment of microbial diversity before the start of therapy and by SVR12 time. We excluded patients who had received antibiotics in the previous 6 months. Twelve patients were enrolled (6 male, 8 genotype 1 (1 subtype 1a), 4 genotype 2). Fibrosis scores were F0 in 1 patient, F2 in 1 patient, F3 in 4 patients and cirrhosis in the remaining 6 (all in Child-Pugh class A). All were treated with DAAs for 12 weeks (5 with Paritaprevir-Ombitasvir-Ritonavir-Dasabuvir, 3 with Sofosbuvir-Ledipasvir, 1 with Sofosbuvir-Ribavirin, 1 with Sofosbuvir-Daclatasvir, 1 with Sofosbuvir-Velpatasvir) and 100% achieved SVR12. In all patients, we observed a trend in reduction of potentially pathogenic microorganisms (i.e., Enterobacteriaceae). Furthermore, a trend of increase in α-diversity was observed in patients by SVR12 compared to baseline. This trend was markedly more evident in patients without liver cirrhosis than in those with cirrhosis. Our study shows that viral eradication obtained with DAA is associated with a trend in restoring the heterogeneity of α-diversity and in reducing the percentage of potentially pathogenic microbial species, although this benefit is less evident in patients with cirrhosis. Further studies with larger sample size are needed to confirm these data.

The Role of CRP POC Testing in the Fight against Antibiotic Overuse in European Primary Care: Recommendations from a European Expert Panel.

Tackling antibiotic resistance represents one of the major challenges in modern medicine, and limiting antibiotics' overuse represents the first step in this fight. Most antibiotics are prescribed in primary care settings, and lower respiratory tract infections (LRTIs) are one of the most common indications for their prescription. An expert panel conducted an extensive report on C-reactive protein point-of-care (CRP POC) testing in the evaluation of LRTIs and its usefulness to limit antibiotic prescriptions. The expert panel stated that CRP POC testing is a potentially useful tool to limit antibiotic prescriptions for LRTI in a community setting. CRP POC must be used in conjunction with other strategies such as improved communication skills and the use of other molecular POC testing. Potential barriers to the adoption of CRP POC testing are financial and logistical issues. Moreover, the efficacy in limiting antibiotic prescriptions could be hampered by the fact that, in some countries, patients may gain access to antibiotics even without a prescription. Through the realization of a better reimbursement structure, the inclusion in standardized procedures in local guidelines, and better patient education, CRP point-of-care testing can represent a cornerstone in the fight against antimicrobial resistance.

Diabetes and SARS-CoV-2 Infection: The Potential Role of Antidiabetic Therapy in the Evolution of COVID-19.

Diabetes mellitus represents one of the most frequent comorbidities among patients with COVID-19, constituting a risk factor for a more severe prognosis than that of non-diabetic patients. However, the pathophysiological mechanism underlying this unfavorable outcome is still not completely clear. The goal of our study was to evaluate the potential role of antidiabetic therapy in the evolution of COVID-19.

Update on the Management of Surgical Site Infections.

Surgical site infections are an increasingly important issue in nosocomial infections. The progressive increase in antibiotic resistance, the ever-increasing number of interventions and the ever-increasing complexity of patients due to their comorbidities amplify this problem. In this perspective, it is necessary to consider all the risk factors and all the current preventive and prophylactic measures which are available. At the same time, given multiresistant microorganisms, it is essential to consider all the possible current therapeutic interventions. Therefore, our review aims to evaluate all the current aspects regarding the management of surgical site infections.

Monoclonal Antibodies against SARS-CoV-2 Infection: Results from a Real-Life Study before the Omicron Surge.

Despite the lightning-fast advances in the management of SARS-CoV after 2 years of pandemic, COVID-19 continues to pose a challenge for fragile patients, who could benefit from early administration of monoclonal antibodies (mAbs) to reduce the risk of severe disease progression. We conducted a prospective study to evaluate the effectiveness of mAbs against SARS-CoV-2 among patients at risk for severe disease progression, namely elderly and those with comorbidities, before the omicron variant surge. Patients were treated with either casirivimab/imdevimab, sotrovimab, or bamlanivimab/etesevimab. The rates and risk factors for clinical worsening, hospitalization, ICU admission and death (unfavorable outcomes) were evaluated. A stratified analysis according to the presence of SARS-CoV-2 IgG was also performed. Among 185 included patients, we showed low rates of unfavorable outcomes (9.2%), which were more frequent in patients with chronic kidney disease (aOR: 10.44, 95% CI: 1.73−63.03; p < 0.05) and basal D-dimer serum concentrations > 600 ng/mL (aOR 21.74, 95% CI: 1.18−397.70; p < 0.05). Patients with negative SARS-CoV-2 serology at baseline showed higher C-reactive protein values compared with patients with positive serology (p < 0.05) and a trend toward a higher admission rate to SICU and ICU compared with patients with positive serology. Our results thus showed, in a real-life setting, the efficacy of mAbs against SARS-CoV-2 before an Omicron surge when the available mabs become not effective.

Nirmatrelvir/Ritonavir and Molnupiravir in the Treatment of Mild/Moderate COVID-19: Results of a Real-Life Study.

Molnupiravir and nirmatrelvir were the first available oral antivirals (OAs) active against SARS-CoV-2. Trials evaluating the efficacy of OAs involved patients unvaccinated and infected with variants different from those currently circulating. We conducted a retrospective study on patients with confirmed SARS-CoV-2 infection treated with OAs during the omicron surge in Italy in order to provide real-life data on the efficacy and safety of OAs during the omicron surge of the COVID-19 pandemic. Among 257 patients, 56.8% received molnupiravir, while 43.2% received nirmatrelvir/ritonavir. Patients in the molnupiravir group were older, had a lower body mass index, and had a higher rate of chronic heart disease than those treated with nirmatrelvir/ritonavir. Three hospitalizations were recorded in the molnupiravir (2.1%) group and one in the nirmatrelvir/ritonavir (0.9%) group. One patient treated with molnupiravir died. The median time to negativity was 8 days in the nirmatrelvir/ritonavir group vs. 10 days in the molnupiravir group, p < 0.01. We recorded 37 ADRs (mainly dysgeusia, diarrhea, and nausea) in 31 individuals (12.1%). Only two patients (0.8%) treated with molnupiravir terminated treatment due to ADRs. In conclusion, in a population of mostly vaccinated patients treated with OAs, we observed a low rate of hospitalization, death, and adverse drug reactions. These rates were lower than those reported in pivotal trials.

COVID-19 Post-Exposure Evaluation (COPE) Study: Assessing the Role of Socio-Economic Factors in Household SARS-CoV-2 Transmission within Campania Region (Southern Italy).

Campania is the sixth poorest region of Italy, and it is the region with the highest income inequality. The secondary attack rates of SARS-CoV-2 among households are found to be substantially heterogeneous among published studies and are influenced by socio-economic factors. We conducted a retrospective study to describe the role of socio-economic factors in the household transmission of SARS-CoV-2 among patients living in Campania Region and referring to "Federico II" Hospital. We interviewed 413 subjects followed-up for COVID-19 between the 8 March 2020 and the 24 May 2021 with the aim to collect demographic, clinical, economic, and social data regarding their household and the index cases. The variables associated with SARS-CoV-2 attack rate higher than 50% among households were higher age (p = 0.023) and higher Charlson Comorbidity Index of the index case (p = 0.023) and, for household characteristics, higher number of families per house (p = 0.02), location of the houses in Naples' suburbs (Chi2 = 5.3, p = 0.02) and in Caserta City area (Chi2 = 4, p = 0.04), and renting the house compared to owning it (Chi2 = 5.83, p = 0.01). This study confirms the finding described by other authors that household transmission of SARS-CoV-2 is correlated with the income inequality of the analyzed geographical area as well as with the indicators of health and economic wealth of the families, and this correlation also applies to the Campania Region.

Pharmacological approaches to prevent vertical transmission of HIV and HBV.

INTRODUCTION: Mother-to-child transmission (MTCT) is mainly responsible for the global pediatric HIV and HBV epidemic. Vertical transmission can be prevented and reduced through a series of interventions at the primary healthcare level, including extensive screening of pregnant women, administration of antivirals or immune-based treatments, counselling on type of delivery and breastfeeding. AREAS COVERED: In this narrative review, approved therapeutic options for the treatment of pregnant women living with HIV or HBV are discussed with special focus on efficacy and safety profiles of each agent or drug class examined. The search was performed using Medline (via PubMed), Web of Science, and Google Scholar to identify studies assessing vertical transmission of both HIV and HBV. EXPERT OPINION: Elimination of MTCT of both infections is firmly endorsed by major global commitments and the integration of tailored preventive interventions into maternal and newborn health services is of strategical importance to achieve this critical target. However, further research centered on antiviral-based and immunization trials among pregnant women is urgently needed to mitigate the risk of maternal and neonatal adverse outcomes, effectively prevent transmission to the offspring and finally eliminate the pediatric HIV and HBV epidemic, one of the key global health challenges of our time.

Impact of an anti-infective screening and monitoring protocol together with infectious disease consultation in preventing infective adverse events in patients treated with anti-CD20/CD52 agents for multiple sclerosis.

BACKGROUND: Monoclonal antibodies have been a milestone in the treatment of multiple sclerosis (MS). Infective complications have been observed in patients on agents targeting lymphoid cells' surface antigens, namely anti-CD52 (alemtuzumab) and anti-CD20 agents (ocrelizumab and rituximab). Despite increasing emerging data, there is no standardized consensus regarding pre-treatment testing, vaccinations, and patient education before and during MS therapy or optimal infection-control strategies. METHODS: We led a retrospective/prospective real-life study to evaluate the effectiveness of a program of screening and prophylaxis for infective adverse events in patients with multiple sclerosis and related disorders treated with drugs directed against CD20/52 antigens. All patients referring to the MS Clinical Care and Research Center, University of Naples "Federico II", who started on alemtuzumab, ocrelizumab or rituximab (off-label use) from 1 November 2015 to 30 June 2019 were recruited. From the 1st of February 2018 patients underwent a microbiological screening and were evaluated by an infectious disease specialist (IDs) before monoclonal antibodies infusion to rule out active infections. We evaluated incidence of infective complications and predictors before (retrospectively)and after (prospectively) the introduction of the above-mentioned anti-infective program. RESULTS: We enrolled 275 patients, 104 retrospectively (pre-intervention group, PRE) and 171 prospectively (post-intervention group, POST). In PRE group, most patients were treated with alemtuzumab (58% vs 32%, p < 0.001), were more frequently DMT naïve (48% vs 36%, p = 0.044) or had received fingolimod in the past (48% vs 28%, p = 0.044) and the follow-up period was longer than in POST group (750 vs 191 days, p < 0.001). In POST group, patients were older (median age 47 vs 42 years, p = 0.030) and mostly received OCR (54% vs 14%, p < 0.001). Lymphopenia at baseline was significantly more commonly observed in PRE arm (47% vs 8%, p < 0.001). A total of 39 patients (38%) in PRE arm and 42 patients (25% in POST) group experienced one or more infections (p = 0.022); severe infections were significantly more common in PRE patients (23% vs 14%, p = 0.022). Our anti-infective program was associated with a lower IAE incidence both at univariate and multivariate analysis (aHR of infective events in PRE group: 3.652 [CI: 9.03-94.19], p < 0.001). Moreover, DMT naïve patients significantly experienced fewer infective complications (aHR: 0.470, [CI: 1.02-2.55], p = 0.040). CONCLUSIONS: A risk mitigation program including infectious disease consultation and standardized screening and prophylactic protocols was effective in reducing infective adverse events in patients receiving anti CD20/CD52 agents for MS.

Inducible Nitric Oxide Synthase (iNOS): Why a Different Production in COVID-19 Patients of the Two Waves?

Profound clinical differences between the first and second waves of COVID-19 were observed in Europe. Nitric oxide (NO) may positively impact patients with Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) infection. It is mainly generated by inducible nitric oxide synthase (iNOS). We studied serum iNOS levels together with serum interleukin (IL)-6 and IL-10 in patients with SARS-CoV-2 infection in the first wave (n = 35) and second wave (n = 153). In the first wave, serum iNOS, IL-6, IL-10 levels increased significantly, in line with the World Health Organization (WHO) score severity, while in the second wave, iNOS did not change with the severity. The patients of the second wave showed lower levels of iNOS, IL-6, and IL-10, as compared to the corresponding subgroup of the first wave, suggesting a less severe outcome of COVID-19 in these patients. However, in the severe patients of the second wave, iNOS levels were significantly lower in patients treated with steroids or azithromycin before the hospitalization, as compared to the untreated patients. This suggests an impairment of the defense mechanism against the virus and NO-based therapies as a potential therapy in patients with low iNOS levels.

COVID-19 prophylaxis in immunosuppressed patients: Beyond vaccination.

Ivan Gentile and Nicola Schiano Moriello discuss the potential of monoclonal antibody prophylaxis against COVID-19 infection in immunocompromised patients.

Monoclonal Antibodies against SARS-CoV-2: Potential Game-Changer Still Underused.

Even several months after the start of a massive vaccination campaign against COVID-19, mortality and hospital admission are still high in many countries. Monoclonal antibodies against SARS-CoV-2 are the ideal complement to vaccination in infected subjects who are at high risk for progression to severe disease. Based on data of the Italian Ministry of Health, in the period April-August 2021, monoclonal antibodies were prescribed to 6322 patients. In the same period, 70,022 patients over 70 years old became infected with SARS-CoV-2. Even considering that all monoclonal antibodies were prescribed to this category of patients, we calculated that only 9% of these subjects received the treatment. Moreover, using efficacy data provided by clinal trials, we estimated the potential benefit in terms of reduction of hospital admissions and deaths. Considering utilisation of monoclonal antibodies in half infected patients over 70 years, we estimated that hospital admissions and deaths might have been reduced by 7666 and 3507, respectively. Finally, we calculated the economic benefit of monoclonal use. In the same scenario (50% use of monoclonal antibodies to patients over 70), we estimated potential savings of USD 117,410,105. In conclusion, monoclonal antibodies were used in a small proportion of patients over 70 in Italy. A more extensive use might have resulted in a marked decrease in hospital admissions, deaths and in conspicuous saving for the health system.

Pneumocystis jirovecii Pneumonia in Non-HIV Patients Recovering from COVID-19: A Single-Center Experience.

OBJECTIVE: to describe a single-center experience of Pneumocystis jirovecii pneumonia (PJP) in non-HIV patients recovering from COVID-19. METHODS: We report the cases of five non-HIV patients with COVID-19 who also developed PJP at a University Hospital. RESULTS: With the exception of one subject, who experienced an atypical and prolonged course of COVID-19, all the patients developed PJP after the clinical resolution of COVID-19 pneumonia. All but one patient had no pre-existing immunosuppressive conditions or other risk factors for PJP development at COVID-19 diagnosis. Nonetheless, following the course of COVID-19 infection, all the patients fulfilled at least one host factor for PJP; indeed, all the patients had received at least 2 weeks of high-dose steroids and three out of five had a CD4+ cell count <200/mm3. CONCLUSIONS: The use of corticosteroids for COVID-19 respiratory impairment seems to be the most common risk factor for PJP, together with viral-induced and iatrogenic lymphopenia. The worsening in respiratory function and the characteristic radiological picture during or after COVID-19 pneumonia should raise the suspicion of PJP, even in immunocompetent patients. PJP primary chemoprophylaxis can be considered in selected high-risk COVID-19 patients, but further studies are needed.

Serum KL-6 Could Represent a Reliable Indicator of Unfavourable Outcome in Patients with COVID-19 Pneumonia.

KL-6 is a sialoglycoprotein antigen which proved elevated in the serum of patients with different interstitial lung diseases, especially in those with a poorer outcome. Given that interstitial pneumonia is the most common presentation of SARS-CoV2 infection, we evaluated the prognostic role of KL-6 in patients with COVID-19 pneumonia. Patients with COVID-19 pneumonia were prospectively enrolled. Blood samples were collected at the time of enrolment (TOE) and on day 7 (T1). Serum KL-6 concentrations were measured by chemiluminescence enzyme immunoassay using a KL-6 antibody kit (LUMIPULSE G1200, Fujirebio) and the cut-off value was set at >1000 U/mL. Fifteen out of 34 enrolled patients (44.1%) died. Patients with unfavourable outcome showed significantly lower P/F ratio and higher IL-6 values and plasmatic concentrations of KL-6 at TOE compared with those who survived (median KL-6: 1188 U/mL vs. 260 U/mL, p < 0.001). KL-6 > 1000 U/mL resulted independently associated with death (aOR: 11.29, p < 0.05) with a positive predictive value of 83.3%. Our results suggest that KL-6 is a reliable indicator of pulmonary function and unfavourable outcome in patients with COVID-19 pneumonia. A KL-6 value > 1000 U/mL resulted independently associated with death and showed good accuracy in predicting a poorer outcome. KL-6 may thus represent a quick, inexpensive, and sensitive parameter to stratify the risk of severe respiratory failure and death.

Pneumocystis jirovecii pneumonia in an immunocompetent patient recovered from COVID-19.

BACKGROUND: Several cases of invasive fungal diseases in patients with COVID-19 have been reported, mostly due to Aspergillus spp., with anecdotic reports of Pneumocystis jirovecii pneumonia (PJP) as co-infections in immunocompromised patients. We describe the first case of PJP in an immunocompetent patient who recovered from COVID-19 pneumonia. CASE DESCRIPTION: Our patient was hospitalized for 18 d for respiratory failure due to Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) pneumonia and successfully treated with continuous positive airway pressure (CPAP) respiratory support, enoxaparin, ceftaroline and intravenous 6 mg of dexamethasone for 10 d, then with oral prednisone tapering. Despite his improved radiological and clinical conditions at discharge, he was admitted again after 18 d for worsening of respiratory conditions. Upon the second admission, a high-resolution CT-scan of the chest showed the development of new ground-glass opacities and P. jirovecii was detected on bronchoalveolar lavage fluid. A therapy with trimethoprim-sulphamethoxazole 20 mg/kg and methylprednisolone 40 mg i.v. bis in die (BID) was started, with improvement of clinical, biochemical and radiological conditions. CONCLUSIONS: COVID-19 patients may have multiple risk factors for development of PJP, in particular lymphopaenia and use of steroids. PJP must be ruled out with direct microbiological methods in patients presenting with radiologic and clinical features of possible or probable PJP, even in immunocompetent hosts.

Novel strategies for the management of bacterial and fungal infections in patients with liver cirrhosis: focus on new antimicrobials.

Introduction: Liver cirrhosis is a frequent condition caused by different etiologies. Bacterial and fungal infections are common complications, representing an independent prognostic stage in patients with cirrhosis, dramatically worsening their clinical outcomes.Areas covered: The present review article addresses manifold points and to this purpose an inductive literature search of MEDLINE database through PubMed was performed. First, it provides an overview on the mechanisms underlying immune disfunctions in patients with cirrhosis, who are prone to develop infections being at higher risk than the general population. Second, commonest types of bacterial and fungal infections in patients with advanced liver disease are described, focusing on their deleterious impact as decompensating events. Third, the rise of multidrug-resistant (MDR) bacteria and fungi as causative agents of infection in cirrhotic subjects is illustrated. Eventually, the most promising novel therapeutic options against MDR pathogens and fungi are reviewed.Expert opinion: The management of bacterial and fungal infections in patients with cirrhosis is difficult, due to the frequent co-existence of renal impairment, low platelet count and other conditions that limit the antimicrobial choice. New antibacterial and antifungal compounds may overcome this issue by providing a better tolerability profile, along with equal or superior efficacy compared with older drugs.

Measles in pregnant women: A systematic review of clinical outcomes and a meta-analysis of antibodies seroprevalence.

OBJECTIVES: Pregnant women represent a category at high risk of severe measles infection, that negatively affects the fetus as well. A systematic review of clinical outcomes of measles infection in gravid subjects and a meta-analysis of antibodies prevalence among pregnant women was conducted. METHODS: MEDLINE and EMBASE databases were searched up to 18 June 2018. The screening focused on: (i) articles describing the outcome of measles in pregnancy, synthesized in a descriptive fashion; (ii) articles addressing the measles seroprevalence in cohorts of gravid women, analysed quantitatively. RESULTS: Twenty-nine articles met inclusion criteria. A total of 420 cases of measles in gravid subjects were described, from 1941 to 2012. Among women, 18 deaths (4.3%) occurred, and the most frequent complication was pneumonia (75/420, 17.9%). Prematurity was the most important complication concerning fetal outcomes (55 out of 410 cases with available data, 13.4%). The random-effects pooled seroprevalence of measles in 20,546 gravid women worldwide was 89.3% (95% CI: 87.3-91.1%), that decreased, although not in a statistically significant way, over time (p = 0.54). CONCLUSIONS: Measles infection in pregnancy is dangerous both for the mother and the foetus. Antibody seroprevalence among gravid women on a global scale is lower than the herd immunity threshold.

Risk of professional accidental exposure to biological agents in health care workers: a retrospective analysis carried out in a southern Italian tertiary hospital.

Worldwide the needlestick injuries of health care workers (HCWs) still represent a major health problem. The authors aimed to evaluate the risk of HCW needlestick injuries in a tertiary university hospital in southern Italy in relation to some HCW characteristics (age, sex, professional profile, work department) and the source of infection. All HCWs of the University Hospital "Federico II" in Naples, Italy, attending the Infectious Diseases Unit after potential accidental contact to blood-borne viruses through needlestick injuries were enrolled during a 22-year period. HCWs underwent clinical analysis and were administered a specific questionnaire to collect (in anonymous fashion) data about age, sex, professional profile and work department. From 1995 to 2016 1,477 needlestick injuries in the same number of people (one accident per person) were recorded by our service. The HCWs were predominately males (n = 806, 55%) and the mean age was 39.4 years (±10.1 SD). The job categories most involved were: physicians (41%), followed by nurses (33%) and healthcare assistants (HCAs, 10%). The incidence proportion was calculated for these highest-risk categories in three defined time points (at the beginning, in the middle and at the end of the study period): 104/2149 (4.86%) in 1995, 41/2498 (1.64%) in 2005 and 25/2057 (1.22%) in 2015. Most injuries occurred in General Surgery (14.21%), Gynecology and Obstetrics (9%) and Pediatrics (6.49%). In about 34% the HCWs had been exposed to HCV infected fluids. Over time, a significant decrease in accidental exposure was recorded for physicians (p= 0.019), nurses (p< 0.0001) and HCAs (p< 0.0001). Our results confirm that some profiles, namely physicians, nurses and healthcare assistants, are still at risk of needlestick injuries, especially in surgical areas, including obstetric wards. Further primary and secondary prevention strategies are needed to decrease the incidence of new cases of needlestick injuries.