丙型肝炎病毒感染相关睡眠障碍的研究进展

据WHO的统计,全球约有1.71亿人罹受丙型肝炎病毒(hepatitis C virus,HCV)的感染[1].伴随HCV的感染,患者常常会出现疲劳、睡眠障碍、抑郁等身心异常的状态.既往有文献报道丙肝患者存在睡眠的问题,但往往淹没在众多肝纤维化及终末期肝病相关的睡眠障碍文献中,鲜有人关注与HCV感染直接相关的睡眠障碍[2].近年来,有少量的文献致力于慢性丙型肝炎睡眠障碍的探讨,让人惊讶的是睡眠问题在慢性丙肝患者中存在着很大程度的普遍性,有证据提示其可能独立于干扰素的治疗.对HCV感染相关睡眠障碍的研究可能会为慢性丙型肝炎的发生、发展及转归提供新的研究思路,也有利于提高患者生活质量,优化现有的治疗方案.     

Hepatitis C virus reinfection after liver transplant: New chances and new challenges in the era of direct-acting antiviral agents

The first interferon-free regimens have been approved for the treatment of patients with chronic hepatitis C virus(HCV). In the liver transplant(LT) setting, these regimens are expected to have an important effect, because graft loss due to HCV recurrence is a serious problem after LT. The response to the hitherto conventional treatment with pegylated interferon and ribavirin is poor. The significantly better responserates achieved with boceprevir-based and telaprevirbased triple therapy have led to better graft and patient survival rates, but severe drug interactions with immunosuppressants limit the feasibility of this therapy for LT patients. With the approval of sofosbuvir in January 2014, of simeprevir in May 2014, and of daclatasvir in August 2014, three antiviral agents are now available and promise to be applicable without relevant adverse effects or negative interactions with immunosuppressants. Thus, 2014 marks the beginning of a new era of treatment options for HCV recurrence after LT. Although safety and efficacy studies of several interferon-free regimens for patients with HCV recurrence after LT have achieved good preliminary results, reports of clinical experiences with LT patients are scarce. The lack of randomized studies, the small number of enrolled and carefully selected patients, and the heterogeneity of these studies make the results questionable. Real-life experiences are eagerly awaited so that clinicians can estimate the usefulness and the pitfalls of these new regimens. Additionally, the high costs of these agents may limit their accessibility for many patients. The aim of this review is to summarize the current experience with and the expectations of the new direct-acting antiviral agents for LT patients.     

Recurrent hepatitis C after liver transplant

End stage liver disease from hepatitis C is the most common indication for liver transplantation in many parts of the world accounting for up to 40% of liver transplants. Antiviral therapy either before or after liver transplantation is challenging due to side effects and lower efficacy in patients with cirrhosis and liver transplant recipients, as well as from drug interactions with immunosuppressants. Factors that may affect recurrent hepatitis C include donor age, immunosuppression, IL28B genotype, cytomegalovirus infection, and metabolic syndrome. Older donor age has persistently been shown to have the greatest impact on recurrent hepatitis C. After liver transplantation, distinguishing recurrent hepatitis C from acute cellular rejection may be difficult, although the development of molecular markers may help in making the correct diagnosis. The advent of interferon free regimens with direct acting antiviral agents that include NS3/4A protease inhibitors, NS5B polymerase inhibitors and NS5A inhibitors holds great promise in improving outcomes for liver transplant candidates and recipients.     

Pharmaceutical management of hepatitis B and C in liver and kidney transplant recipients

The combination of hepatitis B immune globulin with entecavir or tenofovir (at least for a certain period of time) seems to be the most reasonable prophylaxis against recurrent hepatitis B after liver transplantation. Entecavir represents an attractive option for treatment of naïve kidney transplant recipients, because of its high efficacy and the low rates of resistance. However antiviral treatment should be individualized in the view of kidney function and the previous resistance. To date, new captivating therapeutic strategies could make interferon-free regimens viable for treatment of hepatitis C virus positive liver transplant recipients. The recent combinations of sofosbuvir with simeprevir or daclatasvir or ledipasvir plus/minus ribavirin have boosted the on treatment and sustained virological response to rates approaching 100% within liver transplant recipients with recurrent chronic hepatitis C (CHC). Preliminary data showed that the second generation direct oral antivirals could result to high treatment rates of recurrent CHC in kidney transplant recipients as well. Ongoing studies will clarify the optimal treatment of recurrent CHC in kidney transplant recipients.     

Impact of immunosuppression minimization and withdrawal in long-term hepatitis C virus liver transplant recipients

AIM: To investigate the effects of different immunosuppressive regimens and avoidance on fibrosis progression in hepatitis C virus (HCV) liver transplant (LT) recipients.METHODS: We retrospectively compared the liver biopsies of well-matched HCV LT recipients under calcineurin inhibitors (CNI group, n = 21) and mycophenolate (MMF group, n = 15) monotherapy, with those patients who successfully withdrawn immunosuppression (IS) therapy from at least 3 years (TOL group, n = 10). To perform the well-matched analysis, all HCV transplanted patients from December 1993 were screened. Only those HCV patients who reached the following criteria were considered for the analysis: (1) at least 3 years of post-operative follow-up; (2) patients with normal liver graft function under low dose CNI monotherapy (CNI group); (3) patients with normal liver graft function under antimetabolite (Micophenolate Mofetil or coated mycophenolate sodium) monotherapy (MMF group); and (4) recipients with normal liver function without any IS. We excluded from the analysis recipients who were IS free or under monotherapy for < 36 mo, recipients with cirrhosis or with unstable liver function tests.RESULTS: Thirty six recipients were enrolled in the study. Demographics, clinical data, time after LT and baseline liver biopsies were comparable in the three groups. After six years of follow-up, there was no worsening of hepatic fibrosis in the MMF group (2.5 ± 1.5 Ishak Units vs 2.9 ± 1.7 Ishak Units, P = 0.5) and TOL group (2.7 ± 10.7 vs 2.5 ± 1.2, P = 0.2). In contrast, a significant increase in the fibrosis score was observed in the CNI group (2.2 ± 1.7 vs 3.9 ± 1.6, P = 0.008). The yearly fibrosis progression rate was significantly worse in the CNI group (0.32 ± 0.35) vs MMF group (0.03 ± 0.31, P = 0.03), and TOL group (-0.02 ± 0.27, P = 0.02). No differences have been reported in grading scores for CNI group (2.79 ± 1.9, P = 0.7), MMF group (3.2 ± 1.5, P = 0.9) and TOL group (3.1 ± 1.4, P = 0.2). Twenty four patients were treated with low dose ribavirin (8 TOL, 7 MMF, 9 CNI). The hepatitis C titers were comparable in the three groups. No episodes of rejection have been reported despite differences of liver function test in the three groups during the observational period.CONCLUSION: IS withdrawal and MMF monotherapy is safe and seems to be associated with the slowest fibrosis progression in HCV LT recipients.     

Impact of utilization of hepatitis C positive organs in liver transplant: Analysis of united network for organ sharing database

BACKGROUNDThe utility of hepatitis C virus (HCV) organs has increased after the Food and Drug Administration approval of direct acting anti-viral (DAA) medications for the HCV treatment. The efficacy of DAA in treating HCV is nearly 100%. AIMTo analyze the United Network for Organ Sharing (UNOS) database to compare the survival rates between the hepatitis C positive donors and negative recipients and hepatitis C negative donors and recipients. METHODSWe analyzed the adult patients in UNOS database who underwent deceased donor liver transplant from January 2014 to December 2017. The primary endpoint was to compare the survival rates among the four groups with different hepatitis C donor and recipient status: (Group 1) Both donor and recipient negative for HCV (Group 2) Negative donor and positive recipient for HCV (Group 3) Positive donor and negative recipient for HCV (Group 4) Both positive donor and recipient for HCV. SAS 9.4 software was used for the data analysis. Kaplan Meier log rank test was used to analyze the estimated survival rates among the four groups. RESULTSA total of 24512 patients were included: Group 1: 16436, Group 2: 6174, Group 3: 253 and Group 4: 1649. The 1-year (Group 1: 91.8%, Group 2: 92.12%, Group 3: 87%, Group 4: 92.8%), 2-year (Group 1: 88.4%, Group 2: 88.1%, Group 3: 84.3%, Group 4: 87.5%), 3-year (Group 1: 84.9%, Group 2: 84.3%, Group 3: 75.9%, Group 4: 83.2%) survival rates showed no statistical significance among the four groups. Kaplan Meier log rank test did not show any statistical significance difference in the estimated survival rates between Group 3 vs all the other groups. CONCLUSIONThe survival rates in hepatitis C positive donors and negative recipients are similar as compared to both hepatitis C negative donors and recipients. This could be due to the use of DAA therapy with cure rates of nearly 100%. This study supports the use of hepatitis C positive organs in the selected group of recipients with and without HCV infection. Further long-term studies are needed to further validate these findings.     

Management of telaprevir-based triple therapy for hepatitis C virus recurrence post liver transplant

AIM: To characterize management of telaprevir (TVR)-based triple therapy of hepatitis C virus (HCV) reinfection after liver transplantation (LT).METHODS: We retrospectively analyzed safety and efficacy of telaprevir - based triple therapy in a single center cohort of 19 patients with HCV genotype (GT) 1 recurrence after LT, with respect to factors possibly predicting sustained viral response (SVR) or non-SVR. All patients were treated with TVR, pegylated (PEG) and ribavirine (RBV) for 12 wk followed by a dual phase with PEG/RBV for 12 wk in 7 patients and for 36 wk in 5 patients.RESULTS: In total 11/19 (58%) of patients achieved a sustained response. All (11/11) SVR patients showed a rapid viral response at treatment weeks 4 and 11/14 rapid virological response (RVR) patients achieved SVR. Notably, all (7/7) patients who completed 48 wk of therapy and 80% (4/5) patients who completed 24 wk of therapy achieved SVR24. Treatment failure was significantly (P > 0.049) more frequent in GT1a infection (5/7) compared to GT1b (3/12) infection and was associated with emergence of resistance-associated mutations in the NS3 protease domain. Bilirubin level at baseline is also related to SVR (P > 0.030). None of the patients had to discontinue treatment due to side effects.CONCLUSION: RVR, GT and bilirubin are clearly related to achievement of SVR. Providing a thorough patient selection and monitoring, a full course of TVR-based triple therapy in LT patients is feasible and achieves high SVR rates.     

Role of zinc supplementation in the management of chronic liver diseases: A systematic review and meta-analysis

Introduction and objectivesZinc deficiency has been associated with poor prognosis in chronic liver disease. This systematic review and meta-analysis aimed to evaluate the role of zinc supplementation in the management of chronic liver diseases.Materials and methodsWe searched MEDLINE, LILACS, EMBASE, and Cochrane CENTRAL databases from inception to August 2018. We included randomized controlled trials evaluating adult patients with chronic liver disease of any etiology receiving zinc supplementation. Studies with other designs or evaluating chronic conditions other than liver disease were excluded. Two reviewers independently screened and extracted data from eligible studies. Study quality was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomized studies.ResultsOf 1315 studies screened, 13 were included. Six assessed chronic hepatitis C treatment, with a relative risk of 0.83 indicating no protective effect of zinc supplementation on the improvement of sustained virological response. Three evaluated response to hepatic encephalopathy treatment, with a relative risk of 0.66 indicating a favorable effect of zinc supplementation on clinical improvement of this condition. Of four studies evaluating the management of cirrhosis, two analyzed the effect of zinc supplementation on serum albumin levels, with no statistical difference between zinc and placebo groups.ConclusionsClinical trials assessing zinc supplementation in liver diseases do not show benefits in terms of clinical improvement or disease halting. There are possible benefits of zinc supplementation on hepatic encephalopathy, however, this is based on limited evidence. This research question is still open for evaluation in larger, well-designed, clinical trials.     

Prevention of hepatitis B recurrence in liver transplant patients using oral antiviral therapy without long-term hepatitis B immunoglobulin

Background

Small studies have suggested that nucleos(t)ide analogue therapy (NAT) with reduced hepatitis B immunoglobulin (HBIG) duration may be efficacious in preventing post-liver transplantation (LT) HBV recurrence.

Objectives

This larger study evaluates the use of NAT with short term (< 6 mo) or no HBIG for prevention of post-LT HBV recurrence.

Patients and Methods

All HBV patients undergoing LT at a university transplant center between 2002 and 2007 were identified retrospectively. Patient demographics, medication regimen, and adverse events were noted. The primary endpoint was HBV recurrence and secondary endpoints were graft and patient survival.

Results

28 study patients were identified. Of these 28 patients, 4 (14%) received no HBIG, 6 (22%) received only inpatient HBIG, and 18 (64%) received inpatient HBIG and outpatient HBIG. 16 of the 28 patients (57%) received combination NAT and 12 patients (43%) received single NAT. At a median time of 15.5 months (range 9-24 months) post-LT, 4 of the 28 patients (14%) had recurrent HBV. Of those patients with recurrent HBV, 3 received both inpatient and outpatient HBIG and 1 received no HBIG. All cases of HBV recurrence were associated with noncompliance.

Conclusions

NAT with short-term or no HBIG was efficacious and safe in preventing post-LT HBV. All compliant patients were HBV-free, including 9 patients who received no HBIG or only inpatient HBIG. Additional studies using NAT without HBIG appear justified.     

Treatment modalities for hypersplenism in liver transplant recipients with recurrent hepatitis C

Hepatitis C is the most common indication for orthotopic liver transplantation in the United States. Unfortunately,hepatitis C recurs universally in the transplanted liver and is the major cause of decreased graft and patient survival. The combination therapy of interferon and ribavirin has been shown to be the most effective therapy for recurrent hepatitis C. However, pre- and post-transplant hypersplenism often precludes patients from receiving the antiviral therapy. Splenectomy and partial splenic embolization are the two invasive modalities that can correct the cytopenia associated with hypersplenism. In this report we review the two treatment options, their associated outcomes and complications.     

Risk factors for deterioration of long-term liver function after radiofrequency ablation therapy

AIM:To identify factors that influence long-term liver function following radiofrequency ablation(RFA)in patients with viral hepatitis-related hepatocellular carcinoma.METHODS:A total of 123 patients with hepatitis B virus-or hepatitis C virus-related hepatocellular carcinoma(HCC)(n=12 and n=111,respectively)were enrolled.Cumulative rates of worsening Child-Pugh(CP)scores(defined as a 2-point increase)were examined.RESULTS:CP score worsening was confirmed in 22patients over a mean follow-up period of 43.8±26.3mo.Multivariate analysis identified CP class,platelet count,and aspartate aminotransferase levels as significant predictors of a worsening CP score(P=0.000,P=0.011 and P=0.024,respectively).In contrast,repeated RFA was not identified as a risk factor for liver function deterioration.CONCLUSION:Long-term liver function following RFA was dependent on liver functional reserve,the degreeof fibrosis present,and the activity of the hepatitis condition for this cohort.Therefore,in order to maintain liver function for an extended period following RFA,suppression of viral hepatitis activity is important even after the treatment of HCC.     

Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients

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Different behaviour of BK-virus infection in liver transplant recipients

Polyomavirus BK(BKV) infects up to 90% of the general population. After primary infection, occurring early during childhood, a state of non-replicative infection is established in the reno-urinary tract, without complications for immunocompetent hosts. In immunocompromised individuals, particularly transplanted patients, asymptomatic BKV viremia and/or viruria can be observed. Renal grafts may also be sources of infection as BKV prefers kidneys rather than other solid organs for transplantation such as the liver. The mechanism behind the higher incidence of BKV infection in kidney transplant patients, compared to liver or heart transplantation, is unclear and the prevalence of BKV infection in non-renal solid organ transplants has not been yet thoroughly investigated. We evaluated the prevalence of Polyomavirus BK infection among liver transplant recipients. A Pub Med search was conducted using the terms BKV infection AND liver transplant recipients; BKV AND non-renal solid organ transplant*; BKV infection AND immunosuppression; the search was limited to title/abstract and English-language articles published from 2000, to March 2015. Eleven relevant studies suggest that the prevalence of BKV viruria and/or viremia among liver transplant recipients is less than that reported in kidney or heart transplant recipients, except when chronic kidney disease(CKD) is present at the same time. Data also suggest that viruric and viremic patients have higher levels of serum creatinine than BKV negative patients. Moreover, no specific immunosuppressive drugs are associated with the onset of BKV nephropathy. The comorbidity of transplantation and CKD could play a major role in promoting BKV replication.     

Hepatitis B and C infection and liver disease trends among human immunodeficiency virus-infected individuals

AIM:To examine trends in and correlates of liver disease and viral hepatitis in an human immunodeficiency virus (HIV)-infected cohort. METHODS:The multi-site adult/adolescent spectrum of HIV-related diseases (ASD) followed 29 490 HIVinfected individuals receiving medical care in 11 U.S. metropolitan areas for an average of 2.4 years,and a total of 69 487 person-years,between 1998 and 2004. ASD collected data on the presentation,treatment,and outcomes of HIV,including liver disease,hepatitis screening,and he...     

De novo autoimmune hepatitis in liver transplant: State-of-the-art review

In the two past decades, a number of communications, case-control studies, and retrospective reports have appeared in the literature with concerns about the development of a complex set of clinical, laboratory and histological characteristics of a liver graft dysfunction that is compatible with autoimmune hepatitis. The de novo prefix was added to distinguish this entity from a pre-transplant primary autoimmune hepatitis, but the globally accepted criteria for the diagnosis of autoimmune hepatitis have been adopted in the diagnostic algorithm. Indeed, de novo autoimmune hepatitis is characterized by the typical liver necroinflammation that is rich in plasma cells, the presence of interface hepatitis and the consequent laboratory findings of elevations in liver enzymes, increases in serum gamma globulin and the appearance of nonorgan specific auto-antibodies. Still, the overall features of de novo autoimmune hepatitis appear not to be attributable to a univocal patho-physiological pathway because they can develop in the patients who have undergone liver transplantation due to different etiologies. Specifically, in subjects with hepatitis C virus recurrence, an interferon-containing antiviral treatment has been indicated as a potential inception of immune system derangement. Herein, we attempt to review the currently available knowledge about de novo liver autoimmunity and its clinical management.     

A Case Report of Alloimmune Hepatitis after Direct-acting Antiviral Treatment in a Liver Transplant Patient

Direct-acting antiviral (DAA) therapy is often well-tolerated, and adverse events from DAA therapy are uncommon. We report a case of a woman who underwent orthotopic liver transplant for chronic hepatitis C infection and later developed alloimmune hepatitis shortly after starting DAA therapy for recurrent hepatitis C infection. The patient developed acute alloimmune hepatitis approximately 2 weeks after starting treatment with sofosbuvir, velpatasvir, and voxilaprevir. This case report proposes a dysregulation of immune surveillance due to the DAA stimulation of host immunity and rapid elimination of hepatitis C viral load as a precipitating factor for the alloimmune process, leading to alloimmune hepatitis in a post-transplant patient who starts on DAA.     

Prevalence and risk factors for sleep disordered breathing in a Puerto Rican middle-aged population

Background  The Berlin Questionnaire [an outcome of a primary care physicians’ conference held in Berlin, Germany, in 1996 that was created to identify patients at high risk for sleep disordered breathing (SDB)] was administered to a representative sample of middle-age population in Puerto Rico in order to document the prevalence of SDB and its associated risk factors. Materials and methods  The island was divided in six regions to maintain heterogeneity and to have a representative sample of the population per region. Puerto Rican subjects between 30–60 years old were recruited in shopping malls, and questionnaires were filled. For each subject, body weight, neck circumference, and height were measured. Information regarding the diagnosis of hypertension was based upon a positive or negative response from study subject in a questionnaire. Data was collected for 6 months. Results  A total of 290 subjects, all of Puerto Rican origin, were interviewed. Fifty-eight percent of the evaluated sample was found at high risk of SDB. Being male, hypertensive, and obese were the strongest risk factors for the development of SDB. In women, a neck size above 15 cm was a significant risk factor. Conclusions  This is the first time a prevalence study for SDB is done among a representative sample of subjects of Puerto Rican origin. It is the first step in documenting how SDB affects this ethnic group. Presented in part at the American Thoracic Society annual meeting, San Francisco, CA, May 2001.