Angela Londero

Impact of new treatment options for hepatitis C virus infection in liver transplantation

Liver transplant candidates and recipients with hepatitis C virus (HCV)-related liver disease greatly benefit from an effective antiviral therapy. The achievement of a sustained virological response before transplantation can prevent the recurrence of post-transplant HCV disease that occurs universally and correlates with enhanced progression to graft cirrhosis. Previous standard-of-care regimens (e.g., pegylated-interferon plus ribavirin with or without first generation protease inhibitors, boceprevir and telaprevir) displayed suboptimal results and poor tolerance in liver transplant recipients. A new class of potent direct-acting antiviral agents (DAA) characterized by all-oral regimens with minimal side effects has been approved and included in the recent guidelines for the treatment of liver transplant recipients with recurrent HCV disease. Association of sofosbuvir with ribavirin and/or ledipasvir is recommended in liver transplant recipients and patients with decompensated cirrhosis. Other regimens include simeprevir, daclatasvir, and combination of other DAA. Possible interactions should be monitored, especially in coinfected human immunodeficiency virus/HCV patients receiving antiretrovirals.

Pharmacokinetic Interaction Between Everolimus and Antifungal Triazoles in a Liver Transplant Patient

Objective: TO describe the management of a pharmacokinetic interaction between azole antifungals (fluconazole and voriconazole) and everolimus in a patient who underwent an orthotopic liver transplant. Case Summary: A 65-year-old male who received an orthotopic liver transplant experienced an iatrogenic retroperitoneal duodenal perforation on postoperative day 55. His condition was subsequently complicated by severe sepsis and acute renal failure. Intravenous fluconazole 400 mg, followed by 100 mg every 24 hours according to impaired renal function, was immediately started; to avoid further nephrotoxicity, immunosuppressant therapy was switched from cyclosporine plus mycophenolate mofetil to oral everolimus 0.75 mg every 12 hours. Satisfactory steady-state minimum concentration (Cmin) of everolimus was achieved (∼5 ng/mL). On day 72 posttransplant, because of invasive aspergillosis, antifungal therapy was switched to intravenous voriconazole 400 mg every 12 hours on the first day, followed by 200 mg every 12 hours; to prevent drug toxicity, the everolimus dosage was promptly lowered to 0.25 mg every 24 hours. At that time, the everolimus Cmin averaged approximately 3 ng/mL. The concentration/dose ratio of everolimus (ie, Cmin reached at steady-state for each milligram per kilogram of drug administered) was markedly lower during fluconazole versus voriconazole cotreatment (mean ± SD, 3.49 ± 0.29 vs 11.05 ± 0.81 ng/mL per mg/kg/daily; p < 0.001). Despite intensive care, the patients condition continued to deteriorate and he died on day 84 posttransplant Discussion: Both azole antifungals were considered probable causative agents of an interaction with everolimus according to the Drug Interaction Probability Scale. The Interaction is due to the inhibition of CYP3A4–mediated everolimus clearance. Of note, prompt reduction of the everolimus dosage since the first azole coadministration, coupled with intensive therapeutic drug monitoring, represented a useful strategy to prevent drug overexposure. Conclusions: Our data suggest that during everolimus-azole cotreatment, a dose reduction of everolimus is needed to avoid overexposure. According to the different inhibitory potency of CYP3A4 activity, the reduction should be lower during fluconazole than during voriconazole cotreatment.

Long-Term Outcomes of Orthotopic Liver Transplantation in Human Immunodeficiency Virus–Infected Patients and Comparison With Human Immunodeficiency Virus–Negative Cases

Human immunodeficiency virus (HIV) positivity is no longer a contraindication for orthotopic liver transplantation (OLT) due to the efficacy of antiretroviral therapy. The aim of this study was to compare OLT among HIV-positive and HIV-negative cohorts; the results were also stratified for hepatitis C virus (HCV) coinfection. Between 2004 and 2009, all HIV-infected patients undergoing OLT from heart-beating deceased donors (n=27) were compared with an HIV-negative cohort (n = 27). The pure HCV infection rate was similar between HIV-positive and HIV-negative subjects (63% each). HIV-positive recipients were younger (P=.013). The CD4 count for HIV-positive subjects was 376 ± 156 at transplantation. The mean model for end-stage liver disease (MELD) score at transplantation was 15 ± 7 in both groups (P=.92). No differences were observed for donor age (P=.72) or time on the waiting list (P=.56). The median follow-up was 26 (range, 1-64) and 27 months (range, 1-48) for HIV and non-HIV recipients, respectively (P=.85). The estimated 1-, 3-, and 5-year patient and graft survival rates were 88%, 83%, and 83% versus 100%, 73%, and 73% (P=.95), and 92%, 87%, and 87% versus 95%, 88%, and 88% (P=.59) for HIV and non-HIV cases, respectively. HIV/HCV-coinfected patients were younger, namely 47 (range, 40-53) versus 52 years (range, 37-68; P=.003), and displayed lower MELD scores at transplantation compared with HCV-mono-infected patients 10 (range, 7-19) versus 17 (range, 8-30) (P=.008). For HIV/HCV-coinfected and HCV-mono-infected cases the estimated 1-, 3-, and 5-year patients and graft survival rates were respectively 93%, 76%, and 76% versus 100%, 70%, and 60% (P=.99) and 93%, 84%, and 84% versus 100%, 70%, and 60% (P=.64), respectively. No difference was observed in the histological severity of HCV recurrence. In conclusion, under specific, well-determined conditions, OLT can be a safe, efficacious procedure in HIV patients.

Human granulocytic anaplasmosis in northeastern Italy

Abstract:  Sporadic cases of human granulocytic anaplasmosis (HGA) have been reported in areas with a high prevalence of tick‐borne diseases (TBDs) in Europe. We aimed at estimating the sero‐prevalance of A. phagocytophilum and other TBDs in northeastern Italy in outpatients with a history of recent tick bite or suspected TBD. In the 1‐year study, 79 patients were enrolled and 30 (38%) received a diagnosis of TBD: 24 (30%) with Lyme desease and 5 (6%) with HGE. Our findings indicate the presence of HGA in northernsterm Italy; so, since co‐infection with Lyme disease appeared to be frequent, physicians assessing patients after a tick bite should consider HGA in the diagnosis.

Tickborne encephalitis virus, northeastern Italy.

To the Editor: Approximately 3,000 cases of tickborne encephalitis virus (TBEV) disease are registered annually in Europe (1). In Italy, indigenous TBEV infection cases have been only sporadically recorded from 1975 through 2001; in addition, serologic investigations in populations at risk in northern Italy have shown only a low prevalence of specific antibodies (0.6%–5%) (2,3). A surveillance system for TBEV infections was started after autochthonous TBEV was recognized in late summer and fall 2003 in Friuli-Venezia Giulia (FVG), a small region of northeastern Italy with nearly 1 million inhabitants (4). Surveillance is based on systematic microbiologic screening of all patients referred to the emergency departments of regional hospitals for suspected community-acquired central nervous system infections or fever and headache with a history of tick bite in the past 6 weeks. Screening for TBEV was performed on sera or cerebrospinal fluid (CSF) by enzyme immunoassay (Enzygnost Anti-TBE virus Ig, Dade Behring Marburg GmbH, Marburg, Germany) and repeated on convalescent-phase sera. Demonstration of specific immunoglobulin M (IgM) in serum or CSF in the acute phase or >4-fold rise in serum antibody titer in the convalescent phase was interpreted as an indicator of recent TBEV infection. For surveillance purposes, TBEV infection was defined when hemagglutination-inhibition antibody test and neutralization assay by a reference laboratory confirmed ELISA results (5). Data were collected at a regional reference center, where cases were classified as possible, probable, and confirmed, according to the new TBEV case definition (6). From July 2003 through November 2005, 20 cases of TBEV infection were detected; their demographic, epidemiologic, and clinical characteristics are given in the Table. Cases occurred throughout the year, with a biphasic peak in June and September–November. A biphasic clinical course was reported in 10 patients. The median period between tick bite and date of referral to hospital was 22 days (range 15–46 days). Seventeen cases were classified as confirmed, 2 as probable, and 1 case could not be classified because symptoms started after tick season (December) (6). Two patients were coinfected with Borrelia burgdorferi. Table Demographic, epidemiologic, and clinical data of 20 patients with TBEV infection in Friuli-Venezia Giulia* The most common symptoms were fever, headache, nausea, vomiting, and myalgia; the most common central nervous system signs were stiff neck, irritability, and limb paresis. Five patients only reported headache and fever without neurologic signs. Lumbar puncture, performed in 15 patients, showed mild pleocytosis with neutrophil predominance in 13 patients, elevated protein level in 14 patients, and normal glucose level in all. The clinical syndrome was classified, in accordance with Kaiser et al., into febrile form (4 cases), aseptic meningitis (3 cases), encephalitis (2 cases), meningoencephalitis (8 cases), and meningoencephalomyelitis (3 cases) (7). None of the patients died, but 3 required respiratory support in the intensive care unit. Outcome was favorable for 9 patients; major neurologic sequelae were observed in 6 and minor sequelae in 5. During the past 20 years, TBEV has reemerged in several European areas that had been disease free (1,8). In FVG, which borders disease-endemic areas such as Slovenia and Austria, the first cases of TBEV infection were documented recently (4). Several explanations, in addition to the well-established role of climate change, can be proposed (1). First, in Slovenia, after the end of the Communist regime, recreational activities increased considerably, with the creation of natural parks and hunting grounds, densely populated with deer, chamois, rodents, foxes, and other wild animals that can easily cross national borders (9). Second, after the 1976 earthquake that destroyed a large number of mountain villages in FVG, economic activities were progressively concentrated in the plains of the region, which rapidly increased urbanization of the plains towns. As a consequence, the mountains in the northern part of the region were progressively abandoned by humans and returned to wilderness. A final possible explanation is that TBEV cases were undiagnosed because awareness among local physicians was low; however, this variable likely played a minor role, since a recent serologic survey of persons at high risk (forest rangers) yielded a low positivity ratio (3). If even workers at risk had a low seroprevalence, TBEV cases were likely uncommon in the region. The implementation of a regional active surveillance system allows the highest sensitivity in assessing the epidemiologic features of TBEV infections, which are characterized by highly disease-endemic microfoci in areas free of the problem (10). Precisely defining areas where risk is particularly will lead to optimal use of prevention programs and design of educational programs for residents, tourists, and healthcare workers.