Virus Recurrence Research Articles

Long-Term Follow-up of Liver Transplant Recipients Treated With Direct-Acting Antiviral Agents for Hepatitis C Recurrence After Transplantation

BackgroundTreatment of hepatitis C virus (HCV) recurrence after liver transplantation (LTX) with direct-acting antiviral agents (DAA) is effective and leads to sustained viral response (SVR) in most cases. Long-term effect of HCV elimination on LTX function is not clear. The aim of the study was to evaluate the long-term influence of DAA with HCV on the liver function in LTX recipients. MethodsThe study included 120 LTX patients with HCV recurrence. Before starting DAA therapy, all patients underwent liver biopsy and elastography. Biochemical tests and HCV viremia were assessed at baseline, 4, 12, and 24 weeks and 24 months after the end of treatment (EOT). The study protocol conformed with the Declaration of Helsinki. ResultsIn the HCV genotype 1 (G1) group, 106 patients were treated with ledipasvir/sofosbuvir with ribavirin (RBV), and 3 patients received paritaprevir/ritonavir/ombitasvir/dasabuvir/RBV. All HCV genotype 3 (G3) patients were treated with sofosbuvir/RBV; all HCV genotype 4 (G4) patients were treated with paritaprevir/ombitasvir/RBV. The efficacy of the treatment defined as SVR at week 12 after EOT (SVR12) was 97.3% in G1 group, 75% in G3, and 100% in G4 group. Median alanine (ALT) and aspartate (AST) transaminase before therapy were 44.0 IU/mL and 42.5 IU/mL, respectively. Median ALT and AST at 24 months after EOT were 17 IU/mL and 22 IU/mL, respectively. The lack of transaminases normalization was observed in 10 patients 24 months after EOT. ConclusionThe efficacy of DAA therapy of HCV recurrence after LTX is as high as that reported in randomized clinical trials. It is also associated with the improvement of liver function tests during long-term follow-up.

A retrospective study comparing DALK and PKP in the treatment of necrotizing stromal keratitis.

To compare the clinical outcomes of deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP) in the treatment of necrotizing stromal keratitis (NSK). A retrospective study of NSK patients who underwent keratoplasty between January 2015 and December 2017 in the Third Xiangya Hospital was carried out. Data including preoperative and postoperative best corrected visual acuity (BCVA), intraocular pressure, graft survival rates, corneal endothelial cell density, corneal topography and thickness were reviewed and analyzed by SPSS 23.0 software. Fifty patients were involved. Twenty-five patients received DALK, and the other half received PKP. The average follow-up period was 10.28 ± 5.92months. At the end of the follow-up period, there were no significant differences in postoperative BCVA, recurrence of virus, graft rejection or graft failure between the two groups. There were also no significant differences in average central corneal thickness postoperatively at 3months. However, the average corneal endothelial cell density at 3months was significantly higher in the DALK group (2121.12 ± 450.80cell/mm2 in the DALK group versus 1812.16 ± 340.38cell/mm2 in the PKP group, P = 0.009). Both DALK and PKP could increase visual acuity and prevent the progression of NSK. There were no significant differences between DALK and PKP in postoperative BCVA, rate of rejection, graft failure or recurrence rate. DALK significantly reduced the loss of corneal endothelial cells.

Efficacy of Posttransplant Ledipasvir-Sofosbuvir in the Treatment of Patients Who Have Undergone Chronic Hepatitis C-Related Liver Transplant.

This study investigated the efficacy of ledipasvir-sofosbuvir, a newly developed direct-acting antiviral drug combination for hepatitis C virus infection recurrence in patients who have developed cirrhosis secondary to hepatitis C virus and who have undergone liver transplant. We retrospectively analyzed 27 patients who underwent liver transplant due to hepatitis C virus-related cirrhosis and who received ledipasvir-sofosbuvirfor 12 weeks between January 1, 2016 and December 31, 2017 following transplant procedures conducted at the Inonu University Turgut Ozal Medical Center Gastroenterology Department between January 1, 2008 and December 31, 2017. None of the donors had hepatitis C virus infection. Most donor grafts used in transplants were from children of recipients, with the remaining donated grafts from husbands (7%), nephews (4%), wives (7%), and deceased donors (7%). Twenty patients were ultimately included in the study. Hepatitis C virus genotypes, hepatitis C virus RNA, blood counts, and liver enzyme levels of patients before and at 1, 2, and 6 months after treatment were evaluated. At the end of month 6, in addition to hepatitis C virus RNA levels of all patients decreased to unmeasurable levels, levels of alanine and aspartate aminotransferase and gamma-glutamyltransferase had also significantly decreased (all P < .001). None of the patients experienced a complication that led to cessation of treatment. With its reliability and high success rate, the ledipasvir-sofosbuvir combination is a strongly preferable treatment for patients who have undergone liver transplant due to chronic hepatitis C virus-related cirrhosis and who have virus recurrence posttransplant.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database.

BackgroundProphylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population.MethodsKorean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis.ResultsThe study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence.ConclusionCombination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

Hepatitis B virus recurrence after living donor liver transplantation of anti-HBc-positive grafts: A 22-year experience at a single center.

The use of hepatitis B core antibody (anti-HBc)-positive grafts is one strategy for expanding the donor pool for liver transplantation (LT). The aim of this study was to determine the risk factors associated with hepatitis B virus (HBV) recurrence after living donor LT (LDLT) of anti-HBc-positive grafts. From January 1996 to December 2018, a total of 609 LDLT procedures were performed at our center. A retrospective review was performed for 31 patients (23 males and 8 females; median age = 47 years) who underwent LDLT for HBV-unrelated liver disease from anti-HBc-positive donors. The factors associated with HBV recurrence were evaluated and compared between the HBV recurrence and non-recurrence groups. The median follow-up period after LT was 135 months (range, 6-273 months). Four of 31 patients (12.9%) developed post-LT HBV recurrence. All four cases were HBV-naïve patients (anti-HBc-negative and Hepatitis B surface antibody-negative). The median interval between LDLT and HBV recurrence was 42 months (range, 20-51). The overall actuarial rates of HBV recurrence at 1, 3, 5, 10, and 20 years were 0%, 7.2%, 15.7%, 15.7%, and 15.7%, respectively. Although there were no significant differences between the HBV recurrence and non-recurrence groups, HBV recurrence tended to occur in HBV-naïve recipients (P = 0.093). HBV-naïve status may contribute to HBV recurrence after LDLT for HBV-unrelated liver disease from anti-HBc-positive donors. Careful monitoring for serological HBV markers is needed, particularly in this group.

Low-dose anti-hepatitis B immunoglobulin regimen as prophylaxis for hepatitis B recurrence after liver transplantation.

Combination of anti-hepatitis B immunoglobulin (HBIg) and antiviral nucleotide/nucleoside is the most common regimen for prophylaxis against hepatitis B virus (HBV) recurrence. However, what the optimal regimen is for HBIg administration remains subject to debate. Two hundred and thirty-two HBV patients who had liver transplantation were included in this study. According to the decline rate of HBIg, the patients were divided into quick (group Q, n=95) and slow decline groups (group S, n=137). Quick HBIg decline was defined as anti-HBs titer <200IU/mL at postoperative month (POM) 1, when 24000IU of HBIg was given perioperatively. HBV recurrence was defined as reappearance of hepatitis B surface antigen (HBsAg). After a mean (range) follow-up of 42.2 (24.1-76.8) months, the HBV recurrence rate was 12.1% for all 232 patients. The median (interquartile) HBIg titer was 96.2 (41.0-158.0) IU in group Q patients, compared to 418.0 (298.8-692.8) IU in group S patients at POM 1 (P<.001). For the patients in group Q, 18 patients (18.9%) had HBV recurrence; this was higher than the 10 (7.3%) patients in group S (P=.013). Multivariate analysis showed that quick HBIg decline and hepatocellular carcinoma recurrence were the risk factors for HBV recurrence. Perioperative low-dose HBIg and antiviral nucleotide/nucleoside can effectively prevent HBV recurrence in patients with slow HBIg decline. For patients with quick HBIg decline, the idealized HBIg and antiviral agent regimen should be adjusted to establish an effective regimen as prophylaxis against HBV recurrence.

1023 Early Treatment of Recurrent Hepatitis C Post-Liver Transplant

INTRODUCTION: The rate of hepatitis C virus (HCV) recurrence after liver transplant (LT) is greater than 95% and chronic recurrence is more aggressive in the setting of immunosuppressive therapy (IS) in LT patients. Sustained viral response (SVR) is associated with lower mortality rates related to hepatic and extrahepatic manifestations of HCV including renal disease. Currently, however, there are no clear guidelines for the timing of HCV treatment post LT. The goal of this study is to examine the effects of early HCV treatment post-LT on kidney function, liver function and IS. METHODS: This is a retrospective study of 38 LT patients who received HCV treatment within 1 year between 2015 and 2018. Renal function, hepatic function and immunosuppressive regimens were compared at HCV treatment initiation and when patients achieved SVR post treatment. 86% of patients received a Sofosbuvir based regimen. RESULTS: The study included 38 patients with recurrent HCV post LT. Patients were 79% male, 71% Caucasian, with mean age being 57 [range 33-73]. The mean number of days between LT and HCV treatment initiation was 129 days [range 15-321]. All patients were initiated on treatment within the first year of LT. SVR rate was 100% in patients that were compliant with the regimen. No serious side effects were reported. There was no significant difference in mean pre and post-HCV treatment creatinine or number of patients with GFR &lt; 60-pre/post treatment. There was no significant difference between number of patients on Mycophenolate or Tacrolimus before and after treatment. There was no significant difference in the mean dose of steroids, Azathioprine, Mycophenolate or Tacrolimus before and after HCV treatment. CONCLUSION: In patients completing treatment for recurrent HCV within 1 year of LT as early as 15 days post LT, treatment was well tolerated and effective with 100% SVR rate. There was no significant change in number of patients with Cr &lt; 60 before and after treatment and no significant change in the dose of IS. Further studies will help compare outcomes and effects of HCV treatment within one year post LT vs later particularly on renal function and IS therapy.

IL28B Genetic Variations in Patients with Recurrent Herpes Simplex Keratitis.

Background and objectives: Recurrent herpes simplex keratitis (HSK) is the most common cause of corneal blindness in the developed world. A relationship between host gene polymorphisms and the recurrence of herpes simplex virus (HSV) infection has previously been proposed. Thus, the aim of this study was to investigate a potential association between the IL28B host genotype and recurrent HSK. Materials and Methods: Eighty patients older than 18 years of age of both genders with a history of recurrent herpes simplex labialis (HSL) were considered for inclusion. Seventy-five of these patients were found to be seropositive for HSV-1 and were subsequently enrolled in the study. Twenty-four of the enrolled patients also had a history of recurrent HSK associated with severe corneal scarring and visual acuity deterioration. Total DNA was isolated from whole blood samples. A single-nucleotide polymorphism (SNP) rs12979860 near the IL28B gene on chromosome 19 was genotyped. Results: A significant association was observed between recurrent HSK and two SNPs of the IL28B genotype (CCrs12979860 and CTrs12979860, p < 0.01). The variation CCrs12979860 showed a significantly greater association with HSK (16 out of 26 patients) compared with CTrs12979860 (8 out of 34 patients). Conclusion: Seropositive individuals with a history of recurrent HSK are likely to have the CC IL28B genotype. This genotype may be related to incomplete control of the infection and more frequent periodical viral shedding along the first nerve branch of the trigeminal ganglion, which clinically manifests as recurrent herpes keratitis. The clinical manifestation of recurrent HSV-1 infection seems to be influenced by polymorphism of the IL28B genotype.

The prevalence of viral infections in children with cystic fibrosis in a tertiary care center in Saudi Arabia.

IntroductionStudies have shown that pulmonary exacerbations in cystic fibrosis (CF) patients are associated with respiratory viruses. The most common agent causing viral infections in patients with CF before the age of 3 years is respiratory syncytial virus.ObjectivesTo obtain the prevalence of the different types of viral infection in CF patients and to identify its relation with the type of bacterial infection, (CFTR) mutations and pulmonary function test (PFT).MethodologyA retrospective charts review of 387 patients with CF of all age groups who were screened for the detection of viruses during respiratory exacerbation from the period of January 1, 1984 to June 1, 2016.ResultsA total of 159 CF patients had pulmonary exacerbation and had viral PCR obtained. Fifty-eight patients (36%) had positive viral PCR. Males were more commonly infected in 30/58 patients (52%) compared to females in 28 patients (48%). Forty-five of 58 patients (78%) were alive and 13 patients (22%) died. Rhinovirus was the most frequently reported viral PCR in 33/74 sample (45%). Out of 74 viral PCR, 41 (55.4%) were during the colder seasons (October–February) and 33 (44.5%) during the warmer seasons (March–September). During viral infection and viral recurrence, there was an increase in bacterial colonization specifically of H. influenza and staphylococcus aureus. The most common CFTR mutation for the CF viral infection is: 3120+1G>A in Intron 16 in 11/57 patients (19%). The Eastern Province had the highest viral infection of 24 out of 57 patients (42%). Follow-up PFT post viral infection showed no significant difference in the type and the severity of PFT compared to the initial PFT during the viral illness.ConclusionViral infections contributed to the increase in morbidity and mortality of CF patients in our population, and rhinovirus was the most common causative agent. Viral infections and viral recurrence increased the prevalence of bacterial infection of specific pathogens such as H. influenza and S. aureus. Physicians should be aware to prevent progressive lung damage in CF patients by treating the concomitant viral and bacterial infections. Viral infection may be associated with some common CFTR mutations.

What is stirring in the reservoir? Modelling mechanisms of henipavirus circulation in fruit bat hosts.

Pathogen circulation among reservoir hosts is a precondition for zoonotic spillover. Unlike the acute, high morbidity infections typical in spillover hosts, infected reservoir hosts often exhibit low morbidity and mortality. Although it has been proposed that reservoir host infections may be persistent with recurrent episodes of shedding, direct evidence is often lacking. We construct a generalized SEIR (susceptible, exposed, infectious, recovered) framework encompassing 46 sub-models representing the full range of possible transitions among those four states of infection and immunity. We then use likelihood-based methods to fit these models to nine years of longitudinal data on henipavirus serology from a captive colony of Eidolon helvum bats in Ghana. We find that reinfection is necessary to explain observed dynamics; that acute infectious periods may be very short (hours to days); that immunity, if present, lasts about 1–2 years; and that recurring latent infection is likely. Although quantitative inference is sensitive to assumptions about serology, qualitative predictions are robust. Our novel approach helps clarify mechanisms of viral persistence and circulation in wild bats, including estimated ranges for key parameters such as the basic reproduction number and the duration of the infectious period. Our results inform how future field-based and experimental work could differentiate the processes of viral recurrence and reinfection in reservoir hosts.This article is part of the theme issue ‘Dynamic and integrative approaches to understanding pathogen spillover’.

Non-Invasive Assessment of Graft Fibrosis After Living Donor Liver Transplantation: Is There Still a Role for Liver Biopsy?

Non-invasive methods have evolved as a surrogate for liver biopsy such as indirect markers (aspartate transaminase to platelet ratio index, fibro-α score), transient elastography (TE), and magnetic resonance elastography (MRE).The aim of this study is to prospectively compare the value of MRE, TE, and indirect markers in detecting and staging allograft fibrosis compared to liver biopsies in patients who have undergone living donor liver transplantation for complications related to hepatitis C virus.A total of 31 living donor liver transplantation recipients with hepatitis C virus recurrence underwent a liver biopsy, TE, and MRE within 3 months of a liver biopsy. Fibrosis was assessed according to the biopsy and staged according to Metavir criteria.There was a significant correlation between both MRE and fibro-α scores, as well as histologic classification by liver biopsy (P = .02, .002). The diagnostic accuracy of MRE and fibro-α scores in diagnosing significant fibrosis (F ≥ 3) was measured as the area under the curve (.708 and .833, respectively). Both methods showed good diagnostic performance. TE and aspartate transaminase to platelet ratio index were insignificantly correlated with the degree of fibrosis in liver biopsy (P value of .134, .535). At a cutoff value of 5.5 kPa, MRE predicted graft fibrosis (Metavir stage ≥ 3) with 71.43% sensitivity, 75% specificity, 45.5% positive predictive value, and 90% negative predictive value; at a cutoff value > 1.47, fibro-α scores predicted significant graft fibrosis (Metavir stage ≥ 3) with 85.7% sensitivity and 70.83% specificity, with a positive predictive value of 46.2% and a negative predictive value of 94.4%. These data suggest that non-invasive methods could be considered a reliable tool in assessing significant graft fibrosis post-living donor liver transplantation.

The role of hepatitis B core-related antigen in predicting hepatitis B virus recurrence after liver transplantation.

Hepatitis B core-related antigen (HBcrAg) is a viral marker for the development of cirrhosis and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). However, the relationship between HBcrAg and HBV recurrence after liver transplantation (LT) is unclear. To investigate the correlation of serum HBcrAg level with HBV recurrence post-LT to evaluate the prognostic role of the pre-LT HBcrAg level. This retrospective cohort study enrolled 357 CHB patients who received LT for a median of 36.6months. Univariate and multivariate analyses and time-dependent receiver operating characteristic (ROC) curves for markers associated with HBV recurrence were analysed. 48 patients (13.4%) had HBV recurrence after LT. HBcrAg, detectable HBV DNA, HCC and HCC recurrence wereassociated with HBV recurrence. In a multivariate analysis, HBcrAg level was independently associated with HBV recurrence, and the relationship between HBcrAg level and incident HBV recurrence was significant and graded (HR: 3.17 per unit; 95% CI: 1.97-5.11; P for trend<.001). Additionally, HBcrAg level was superior to HBV DNA level in predicting HBV recurrence bytime-dependentROCanalysis. Patients with an HBcrAg≥5.0 logU/mL had a significantly higher 5-year cumulative recurrence rate than those with an HBcrAg<5.0 logU/mL (37.6% vs 6%, P<.001); the adjusted hazard ratio was 5.27 (95% CI 2.47-11.25, P<.001). An elevated serum HBcrAg level was independently associated with the risk of HBV recurrence in patients with CHB after LT.

Aprémilast

Hepatitis C is a common indication for liver transplantation (LT). Hepatitis C virus (HCV) recurrence is universal in viremic patients. This recurrence is frequently very aggressive, with graft loss in less than 5 years. Our aim is to detect which factors are related to worse fibrosis at 1 year post-LT.Records of all HCV-positive transplanted patients in Hospital Universitario Nuestra Señora de la Candelaria from 1996 to 2014 were collected. The variables analyzed were donor and recipient age and gender, hypertension, diabetes, viral genotype, viral load at LT, hepatocellular carcinoma in the explant, anticoagulation or antiplatelet treatment, year of transplantation, and mean levels of tacrolimus in the first month. Severe recurrence was defined as fibrosis F3 by biopsy, liver stiffness > 9.5 kPa by transient elastography, or hepatic venous pressure gradient > 5 mm Hg at 1 year post-LT. Univariate and multivariate analyses were performed.From a sample of 112 patients, 88 patients met inclusion criteria. Mean recipient age was 52.8 ± 8.0 years and 70.5% were men. Mean donor age was 46.4 ± 16.1 years and 59.1% were men. Severe recurrence occurred in 23.9%. Univariate analyses showed 3 variables were statistically significant: donor age (P = .03), recipient age (P = .008), and presence of hepatocellular carcinoma (P = .01). Only the 2 first variables remained significant in the multivariate model (P = .009 and P = .044 respectively). Hepatocellular carcinoma was probably related to older recipients becoming a confounding factor.In our study, donor and recipient age both conferred a worse prognosis in terms of fibrosis progression in patients with liver transplant due to HCV.

Detection of antibodies to the hepatitis C virus using up-converting nanoparticles − Based lateral flow immunoassay

Immunoglobulin G4 (IgG4)-associated autoimmune hepatitis (AIH) was recognized as a new disease entity; however, IgG4-associated de novo AIH after the liver transplantation had not been reported yet. Herein we have described a 56-year-old man who developed IgG4 de novo AIH as 1 year–post liver transplantation after receiving pegylated interferon alpha-2a and ribavirin therapy for hepatitis C virus recurrence. The histopathologic evidence showed an aggressive lymphoplasmacytic interface hepatitis with centrilobular necrosis (plasma cells > 30%) and IgG4-positive plasma cells (>10 per high power field). Serum IgG (9220 mg/dL) and IgG4 (3289 mg/dL) were also elevated. Improvement of liver function tests (LFTs) by prednisone and azathioprine therapy are manifested as normalized alanine aminotransferase and IgG levels. IgG4 relates to more severe histological activity; however, it is believed to be a good prognostic predictor of a response to prednisone plus azathioprine therapy especially with early diagnosis and timely management.

Pediatric roots of cytomegalovirus recurrence and memory inflation in the elderly.

The establishment of a lifelong latent infection after resolution of primary infection is a hallmark of cytomegalovirus (CMV) biology. Primary infection with human CMV is possible any time in life, but most frequently, virus transmission occurs already perinatally or in early childhood. Many years or even decades later, severe clinical problems can result from recurrence of infectious virus by reactivation from latency in individuals who undergo immunocompromising medical treatment, for instance, transplant recipients, but also in septic patients without canonical immunosuppression, and in elderly people with a weakened immune system. The diversity of disease manifestations, such as retinitis, pneumonia, hepatitis, gastrointestinal disease, and others, has remained an enigma. In clinical routine, seropositivity for IgG antibodies against human CMV is taken to indicate latent infection and thus to define a qualitative risk of recurrence, but it is insufficient as a predictor for the quantitative risk of recurrence. Early experimental studies in the mouse model, comparing primary infection of neonatal and adult mice, led to the hypothesis that high load of latent viral genomes is a better predictor for the quantitative risk. A prolonged period of virus multiplication in the immunologically immature neonatally infected host increased the risk of virus recurrence by an enhanced copy number of latent virus genomes from which reactivation can initiate. In extension of this hypothesis, one would predict today that a higher incidence of reactivation events will also fuel the expansion of virus-specific T cells observed in the elderly, a phenomenon known as "memory inflation". Notably, the mouse model also indicated a stochastic nature of reactivation, thus offering an explanation for the diversity and organ selectivity of disease manifestations observed in patients. As the infection history is mostly undefined in humans, such predictions from the mouse model are difficult to verify by clinical investigation, and moreover, such questions were actually rarely addressed. Here, we have surveyed the existing literature for reports that may help to retrospectively relate the individual infection history to the risk of virus recurrence and recrudescent organ disease.

Entecavir and other nucleos(t)ide analogs prophylaxis in hepatitis B virus-related liver transplantation: long-term efficacy and safety.

Although hepatitis B virus (HBV) recurrence after liver transplantation (LTx) has been reduced since the application of the combination of hepatitis B immunoglobulin (HBIG) and nucleos(t)ide analogs (NUCs), the optimum regimen to prevent HBV recurrence with LTx favorable outcome is still not clear. The aim was to evaluate the efficacy and safety of NUCs prophylaxis (±HBIG) against HBV recurrence after LTx. This was a retrospective cohort-longitudinal study on 44 HBV-related post-LTx patients on anti-HBV prophylactic therapy. They included the entecavir (ETV)-based (n=34, 30 males) and the other NUC-based (n=10, 7 males) groups±HBIG. The median age was 63.5 (60-70) years in ETV and 62.5 (55-65) years in other NUCs groups. The mean follow-up duration was 6.09±1.83 years in ETV-based group and 6.3±1.89 years in other NUCs-based group. The mean ETV duration was 3.47±3.04 years. In ETV+HBIG patients, none of them developed HBV recurrence throughout the ±8 years. In the 14 patients on ETV+other NUC+HBIG, four developed HBsAg positive and then transformed to HbsAb positive at the end of ±8 years without hepatitis or detectable HBV-DNA. Liver graft function showed nonsignificant difference for ETV-based patients, in comparison with other NUC groups (P=0.09). With subdivision, the graft function was maintained significantly better in ETV+HBIG or other NUCs+HBIG (P=0.04) groups. None of our patients reported NUCs-related complications or adverse effects. ETV and other NUCs were effective and safe as a long-term prophylaxis of HBV recurrence after LTx, leading to a good graft function. HBsAg temporally reappeared in a minority of patients, where all showed HBsAb seroconversion without detectable HBV-DNA or clinical hepatitis.

A systematic review with meta-analysis: Is ribavirin necessary in sofosbuvir-based direct-acting antiviral therapies for patients with HCV recurrence after liver transplantation?

ObjectivesWith the appearance of direct-acting antiviral agents (DAAs), sofosbuvir (SOF)-based DAAs are recommended for patients with hepatitis C virus (HCV) recurrence after liver transplantation (LT). Whether ribavirin (RBV) is needed by patients after LT in combination with SOF-based DAAs remains to be determined. This meta-analysis was conducted to evaluate the necessity of RBV with SOF-based DAAs for post-LT patients. MethodsPubMed, Web of Science, Cochrane Library and EMBASE databases were systematically searched for eligible studies from the databases’ inceptions until November 2018. We accepted the studies that included HCV recurrence in post-LT patients who were treated with SOF-based DAAs ± RBV, and evaluated the rate of sustained virological response 12 weeks (SVR12) after the end of treatment. ResultsTwelve studies, comprising a total of 1466 LT recipients, were included in this study. The pooled SVR12 of these patients was 91% (95% CI: 84% to 95%). There was no statistical difference of SVR12 in the patients treated with SOF-based DAAs + RBV versus –RBV group (risk ratio [RR] = 0.97; 95% CI: 0.92 to 1.03; P = 0.35) by different therapy duration (P = 0.26), with different targets of DAAs (P = 0.13) and in different regions (P = 0.34) but a tendency for a higher incidence of anemia in the +RBV group than in the −RBV group (RR = 5.18; 95% CI: 3.41 to 7.86; p < 0.00001). ConclusionThe addition of RBV may not contribute to a higher SVR rate and could increase the incidence of anemia, so RBV is not necessary in SOF-based DAAs for patients with HCV recurrence after LT.

Direct-acting antiviral agents for liver transplant recipients with recurrent genotype 1 hepatitis C virus infection: Systematic review and meta-analysis.

BackgroundComprehensive evaluation of safety and efficacy of different combinations of direct‐acting antivirals (DAAs) in liver transplant recipients with genotype 1 (GT1) hepatitis C virus (HCV) recurrence remains limited. Therefore, we performed this systematic review and meta‐analysis in order to evaluate the clinical outcome of DAA treatment in liver transplant patients with HCV GT1 recurrence.MethodsStudies were included if they contained information of 12 weeks sustained virologic response (SVR12) after DAA treatment completion as well as treatment related complications for liver transplant recipients with GT1 HCV recurrence.ResultsWe identified 16 studies comprising 885 patients. The overall pooled estimate proportion of SVR12 was 93% (95% confidence interval (CI): 0.89, 0.96), with moderate heterogeneity observed (τ 2 = 0.01, P < 0.01, I 2=75%). High tolerability was observed in liver transplant recipients reflected by serious adverse events (sAEs) with pooled estimate proportion of 4% (95% CI: 0.01, 0.07; τ2 = 0.02, P < 0.01, I 2 = 81%). For subgroup analysis, a total of five different DAA regimens were applied for treating these patients. Sofosbuvir/Ledipasvir (SOF/LDV) led the highest pooled estimate SVR12 proportion, followed by Paritaprevir/Ritonavir/Ombitasivir/Dasabuvir (PrOD), Daclatasvir (DCV)/Simeprevir (SMV) ± Ribavirin (RBV), and SOF/SMV ± RBV, Asunaprevir (ASV)/DCV. There was a tendency for favoring a higher pooled SVR12 proportion in patients with METAVIR Stage F0‐F2 of 97% (95% CI: 0.93, 0.99) compared to 85% (95% CI: 0.79, 0.90) for stage F3‐F4 (P < 0.01). There was no significant difference between LT recipients treated with or without RBV (P = 0.23).ConclusionsDirect‐acting antiviral treatment is highly effective and well‐tolerated in liver transplant recipients with recurrent GT1 HCV infection.

Epidemiological, Clinical, and Laboratory Characteristics of Acute Disseminated Encephalomyelitis in Children: A Retrospective Study.

We aimed to study the precipitating factors, demographic data, clinical and radiological manifestations, electroencephalography and laboratory findings, as well as association with infections, immunization and incidence of relapse of acute disseminated encephalomyelitis (ADEM) in children admitted to Mofid Children Hospital, Tehran, Iran from Mar 2013 to Mar 2016. A 3-yr retrospective review of 29 children with definite final diagnosis of ADEM in Mofid Hospital in Tehran, Iran was performed. The diagnosis was based on specified criteria, including a presumed acute demyelinating process with no history of unexplained neurological symptoms and at least one demyelinating lesion shown on magnetic resonance imaging without evidence of previous destructive white matter lesions. Overall, 29 children diagnosed as ADEM were studied in terms of demographic characteristics, clinical manifestations and laboratory findings in two groups according to their recurrence. The mean age of the patients with recurrence was less than those without it were. It was more common in females but the difference was not statistically meaningful. There was no relationship between the season of the first episode of the disease and the recurrence incidence. Moreover, the relationship between viral infections and recurrence was statistically non-meaningful. No relationship between the recurrence of ADEM and clinical manifestations, radiological and laboratory findings was found. The reason for high rate of recurrence in our patients may be related to the younger age of children in our study.

Determination of Hepatitis B Immunoglobulin Infusion Interval Using Pharmacokinetic Half-life Simulation for Posttransplant Hepatitis B Prophylaxis.

BackgroundProphylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. This study established an individualized HBV prophylaxis protocol, through optimization of hepatitis B immunoglobulin (HBIG) administration, with application of simulative half-life (SHL).MethodsThis study involved five parts: Part 1 developed the SHL estimation method with 20 patients; Parts 2 and 3 assessed the SHL variability and developed a simulation model to apply SHL in 100 patients; Part 4 validated the simulation model in 114 patients, and Part 5 was a cross-sectional study on the current status of HBIG infusion intervals in 660 patients.ResultsIn Part 1, infusion of 10,000 IU HBIG induced add-on rise hepatitis B surface antibody (anti-HBs) titer of 5,252.5 ± 873.7 IU/L, which was 4.4% lower than actual measurement. Mean SHL of 20.0 ± 3.7 days was 2.2% longer than actual measurement. In Part 2, the medians of the intra- and inter-individual coefficient of variation in SHL were 13.5% and 18.5%, respectively. Pretransplant HBV DNA load and posttransplant antiviral therapy did not affect SHL. In Part 3, a simulation model was developed to determine the interval of HBIG infusion, by using SHL. In Part 4, all 114 patients were successfully managed with regular HBIG infusion intervals of ≥ 8 weeks, and the interval was prolonged to ≥ 12 weeks in 89.4%, with a target trough anti-HBs titer ≥ 200 IU/L. In Part 5, 47.4% of our patients received HBIG excessively, at a target trough titer of 500 IU/L.ConclusionSHL estimation using only clinically available parameters seems to be reliably accurate when compared with actual measurements. We believe that SHL estimation is helpful to establish a personalized HBV prophylaxis protocol for optimizing HBIG administration.