Prevalence and clinical consequences of Hepatitis E in patients who underwent liver transplantation for chronic Hepatitis C in the United States.

BACKGROUND: Infection with hepatitis E virus (HEV) in immunocompromised patients can lead to severe liver disease. Treatment options for HEV include peginterferon or ribavirin, routinely also used for the treatment of hepatitis C virus (HCV) infection. We determined the prevalence and clinical consequences of HEV in United States (US) based patients who underwent liver transplantation (LT) for chronic HCV. METHODS: Seroprevalence of HEV in 145 US LT recipients with a history of chronic HCV was determined pre-LT, 1, 3 and 5 years post-LT. All last available samples and all samples in IgM positive patients and post-LT IgG seroconverters were tested for HEV RNA. RESULTS: Overall anti-HEV seroprevalence was 42 %. Five patients were HEV IgM positive pre-LT, one patient had IgM seroconversion post-LT and eight patients had IgG seroconversion post-LT. None of the tested samples were positive for HEV RNA. Eight out of nine of the post-LT seroconverters had been treated for HCV recurrence before or at the moment of seroconversion. CONCLUSIONS: LT recipients in the US are at risk of acquiring HEV. Post-LT HCV treatment with interferons and/or ribavirin may have protected patients against chronic HEV. With the arrival of new direct antiviral agents for the treatment of HCV and the elimination of peginterferon and ribavirin from HCV treatment regimens, the prevalence of chronic HEV in this population may rise again.

The ARRIBA concept: adequate resorption of ribavirin.

BACKGROUND: Adequate ribavirin exposure is essential for optimal sustained virological response (SVR) rates in chronic HCV treatment. It has been proposed that the area under the concentration-time curve up to 4 h after intake of ribavirin (AUC0-4 h) of the first weight-based ribavirin dose should be ≥1.755 mg•h/l to guarantee the highest chance of SVR. Our ARRIBA concept comprises a test dose of ribavirin to select the optimal starting dose to achieve adequate exposure. This study aims to evaluate whether adequate exposure can be achieved after dose advice based on the AUC0-4 h of a single weight-based ribavirin test dose. METHODS: (Formerly) HCV-infected subjects received a single weight-based ribavirin test dose (<75 kg: 400 mg; ≥75 kg: 600 mg) and the AUC0-4 h was calculated. If ribavirin AUC0-4 h was ≥1.755 mg•h/l, subjects received the same dose 4 weeks later; if the AUC0-4 h was <1.755 mg•h/l, an adjusted dose was administered. The ribavirin AUC0-4 h was recorded again. The primary outcome was the proportion of subjects with an AUC0-4 h ≥1.755 mg•h/l after the second dose. RESULTS: A total of 26 subjects were included. The geometric mean (95% CI) ribavirin AUC0-4 h was 1.67 (1.44-1.92) mg•h/l with 9 subjects (35%) reaching the target AUC on day 1. Thus, on day 29, 17 subjects (65%) received an adjusted dose. The geometric mean (95% CI) AUC0-4 h increased to 1.90 (1.62-2.21) mg•h/l and then 16 subjects (62%) had an AUC0-4 h ≥1.755 mg•h/l, which is significantly higher than day 1 (P<0.05). CONCLUSIONS: Our ARRIBA concept of a ribavirin test dose, with dose adjustment if necessary, leads to an increased proportion of patients with an AUC≥1.755 mg•h/l compared to traditional weight-based ribavirin dosing.

Analysis of the transcriptome and immune function of monocytes during IFNα-based therapy in chronic HCV revealed induction of TLR7 responsiveness.

Although in vitro studies have been performed to dissect the mechanism of action of IFNα, detailed in vivo studies on the long-term effects of IFNα on monocytes have not been performed. Here we examined peripheral blood from 14 chronic HCV patients at baseline and 12 weeks after start of IFNα-based therapy. Monocytes were phenotyped by flow-cytometry and their function evaluated upon TLR stimulation and assessed by multiplex cytokine assays. During therapy of HCV patients, monocytes displayed a hyperactive state as evidenced by increased TLR-induced pro-inflammatory cytokine levels, as well as enhanced CD69 and CD83 mRNA and protein expression. Moreover, monocytes from 8 patients at baseline and 12 weeks after start of IFNα-based therapy were transcriptomically profiled by high throughput RNA-sequencing. Detailed RNA-seq analysis of monocytes showed significant ISG mRNA induction during therapy. Importantly, IFNα-based therapy activated TLR7 signaling pathways, as demonstrated by up-regulated expression of TLR7, MyD88, and IRF7 mRNA, whereas other TLR family members as well as CD1c, CLEC4C, and CLEC9A were not induced. The induction of TLR7 responsiveness of monocytes by IFNα in vivo in HCV patients is relevant for the development of TLR7 agonists that are currently under development as a promising immunotherapeutic compounds to treat chronic viral hepatitis.

Multicenter experience using telaprevir or boceprevir with peginterferon and ribavirin to treat hepatitis C genotype 1 after liver transplantation.

The safety, efficacy, and effect on immunosuppression levels of telaprevir (TVR) or boceprevir (BOC) in combination with peginterferon (PEG-IFN) and ribavirin (RBV) in recipients of liver transplantation (LT) with hepatitis C virus (HCV) genotype 1 have not been defined. We report our 3 centers' preliminary experiences with administering triple antiviral treatment protocols containing PEG-IFN, RBV, and TVR or BOC. Patients with biopsy-proven HCV recurrence (METAVIR grade ≥ 3 and/or stage ≥ 2) received TVR with PEG-IFN/RBV for 12 weeks and then PEG-IFN/RBV for 36 weeks or BOC with PEG-IFN/RBV for 44 weeks after 4 weeks of lead-in PEG-IFN/RBV. Maintenance immunosuppression was changed to cyclosporine whenever possible, and the levels were followed closely. PEG-IFN/RBV dose adjustments were based on patients' tolerance. Sixty patients started triple antiviral treatment, and they were followed for up to 66 weeks (mean = 35 weeks); all were followed at least 12 weeks. Thirty of the 35 patients treated with TVR (86%) achieved undetectable HCV RNA levels after an average of 6 weeks, whereas 12 patients (48%) in the BOC-treated group achieved undetectable HCV RNA levels after a mean of 11 weeks. According to an intention-to-treat analysis, 14 of 21 TVR-treated patients (67%) and 10 of 22 patients who received BOC (45%) achieved undetectable HCV RNA levels at week 24 without viral breakthrough at the last follow-up. Cytopenias complicated both regimens; all patients required dose reductions of PEG-IFN and/or RBV or the administration of hematological growth factors. One death occurred in each group on triple antiviral treatment. In conclusion, TVR or BOC combined with PEG-IFN/RBV achieved on-treatment virological response rates of approximately 50% to 60% in patients with recurrent HCV after LT, but significant side effects were common.

Erythropoietin administration suppresses human monocyte function in vitro and during therapy-induced anemia in HCV patients.

Erythropoietin (EPO) is a hormone that controls red blood cell production. Binding of EPO to the EPO-receptor results in increased numbers of red blood cells in the circulation, which makes EPO a potent molecule to treat anemia in various groups of patients. Although numerous studies have examined the clinical effects of EPO, its immunological effects have received less attention. In this study, we examined the immunological effects of EPO on human monocytes. We show that human monocytes express EPO receptor mRNA, and are responsive to EPO in cell culture. In vitro exposure of PBMC from individuals to EPO and the TLR4 ligand LPS showed a significant reduction of monocytes producing IL-6 and TNF, while the frequencies of IL-12p40, IL-10, MIP-1ß and IL-8-producing cells did not change upon incubation with EPO. In addition, EPO did increase the phagocytic activity but did not affect the ability to produce ROS by monocytes. Moreover, we studied eight chronic HCV patients undergoing treatment with peg-IFN and ribavirin, who were administered EPO for treatment-induced anemia. Blood was collected before and 7 days after EPO injection. In 7 patients, we observed a significant decline at day 7 after EPO administration of the frequency of monocytes producing various pro-inflammatory cytokines following stimulation with the TLR4 ligand LPS and the TLR7/8 ligand R848, which is in line with our in vitro findings. Our findings demonstrate an inhibitory effect of EPO on the secretion of effector molecules by monocytes and a stimulatory effect on the phagocytic activity by monocytes.

Clinical implications of chronic hepatitis E virus infection in heart transplant recipients.

BACKGROUND: Recent reports have shown that hepatitis E virus (HEV) infection can become chronic in solid-organ transplant recipients, but few studies have systematically investigated the clinical consequences of this chronic HEV infection in solid-organ transplant (SOT) recipients. METHODS: We have undertaken an in-depth study of 6 chronic HEV-infected heart transplant recipients to gain further insight into the clinical, biochemical and virologic presentation of this disorder. RESULTS: In 6 patients (2.3%) chronic HEV infection, genotype 3, was identified. Immunosuppression in these patients was tacrolimus-based, combined with either everolimus or prednisolone and/or mycophenolate mofetil. Median follow-up after case detection was 26 months (range 21 to 40 months). All chronic HEV cases had elevated liver enzyme values. IgM antibodies at presentation were positive in 2 of 6 (33%) patients. Liver histology in 4 of 6 (67%) patients showed advanced fibrosis within 2 years after infection. One patient spontaneously cleared the HEV infection: 1 after dose reduction of immunosuppressive therapy and 3 during ribavirin therapy. One patient has yet to clear the virus and remains on ribavirin therapy. CONCLUSIONS: Chronic HEV infection in heart transplant (HTx) recipients may lead to rapid fibrosis of the liver. We advise additional HEV RNA screening in solid-organ transplant recipients with elevated liver enzymes, because antibody production is often delayed, as demonstrated in these patients. Dose reduction of immunosuppressive therapy should be the first intervention strategy to achieve viral clearance in chronic HEV-infected immunocompromised patients. Ribavirin treatment should be considered in cases of chronic HEV.

[Encephalitis lethargica in the Netherlands; renewed interest in a mysterious disease]. / Encephalitis lethargica in Nederland: hernieuwde belangstelling voor een mysterieuze ziekte.

In the first half of the 20th century, during the Spanish flu pandemic, more than half a million people died from a mysterious disease sleeping sickness which was named 'encephalitis lethargica'. Despite extensive research, the cause of the disease has not yet been established. In the Netherlands many doctors published cases in the Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine), also when chronic forms of the disease arose. An attempt to treat patients suffering from the chronic disease with levodopa initially had spectacular results but eventually lead to a new disappointment as a result of severe side effects. The experiment was stopped prematurely. Encephalitis lethargica is still being sporadically diagnosed in the 21st century. Recent research suggests that an autoimmune response targeted at the basal ganglia, possibly caused by a streptococcal infection, plays a role in the aetiology of the disease.