Meta-analysis: the dialysis mode and immunological response to hepatitis B virus vaccine in dialysis population

BACKGROUND: Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non-uraemic population. Some authors have claimed that dialysis mode has an impact on the immune response to hepatitis B virus vaccine but consistent information is lacking on this issue. AIM: To evaluate the relationship between dialysis mode and immune response to hepatitis B vaccine in dialysis population by performing a systematic review with a meta-analysis of clinical trials. METHOD: We used the random effects model of DerSimonian and Laird; sources of heterogeneity in effect estimates were explored by performing sensitivity analyses. RESULTS: The relative risk of failure to respond to hepatitis B vaccine among patients who underwent maintenance haemodialysis vs. peritoneal dialysis was the end point of interest. We identified 14 clinical trials involving 1211 unique patients on maintenance dialysis. Pooling of study results did not show a significant decreased risk of response to hepatitis B vaccine among haemodialysis patients (overall risk ratio: 1.0, 95% confidence intervals: 0.92-1.1). The P-value was 0.13 for our test of study heterogeneity. CONCLUSION: There is no significant link between dialysis mode and seroresponse to hepatitis B virus vaccine in dialysis population.     

Meta-analysis: interferon for the treatment of chronic hepatitis C in dialysis patients

BACKGROUND: The efficacy of interferon monotherapy in dialysis patients with chronic hepatitis C remains unclear, although a number of small clinical trials have been published addressing this issue. METHODS AND AIMS: We evaluated the efficacy and safety of initial interferon monotherapy in dialysis patients with chronic hepatitis C by performing a systematic review of the literature with a meta-analysis of clinical trials. The primary outcome was sustained virological response (as a measure of efficacy); the secondary outcome was drop-out rate (as a measure of tolerability). We used the random effects model of Der Simonian and Laird, with heterogeneity and sensitivity analyses. RESULTS: We have identified 14 clinical trials (269 unique patients); two were controlled studies. The mean overall estimate for sustained virological response (SVR) and drop-out rate was 37%[95% confidence interval (CI) 28-48] and 17% (95% CI 10-28), respectively. The most frequent side-effects requiring interruption of treatment were flu-like symptoms (17%), neurological (21%) and gastrointestinal (18%). The overall weighted estimate for SVR in patients with hepatitis C virus genotype 1 was 30.6% (95% CI 20.9-48). In the sub-group of clinical trials (n = 5) with standard interferon administration (3 million units [MUI] thrice weekly, subcutaneous route, 24-week treatment), the overall mean estimate of SVR was 39% (95% CI 25-56). The studies were heterogeneous with regard to SVR and drop-out rate. CONCLUSIONS: Tolerance to initial interferon monotherapy was lower in dialysis than nonuremic patients with chronic hepatitis C. However, more than one-third of haemodialysis patients with chronic hepatitis C have been successfully treated with interferon. Longer duration of interferon monotherapy does not appear to have a beneficial effect on the response rate. Further studies are warranted to define the optimal anti-viral regimen for chronic hepatitis C in dialysis population.     

预防血液透析患者乙型肝炎与丙型肝炎病毒感染的效果观察

目的 采取有效措施预防维持性血液透析患者乙型肝炎、丙型肝炎病毒感染的发生.方法 观察2008年9月至2011年3月在本院行维持性血液透析患者,每6个月化验1次乙型肝炎五项、丙型肝炎抗体指标,共6次.结果 36例维持性血液透析患者未再出现新的乙型肝炎、丙型肝炎病毒感染病例.结论 采取有效措施可预防维持性血液透析患者乙型肝炎、丙型肝炎病毒感染的发生.     

Occult hepatitis B virus infection in dialysis patients: a multicentre survey

BACKGROUND: The epidemiology and clinical significance of occult hepatitis B virus infection (serum hepatitis B surface antigen-negative patients with detectable hepatitis B virus viraemia in serum) remains controversial with only limited information about its prevalence in patients on long-term dialysis. AIM: To address the epidemiology of occult HBV infection in a large cohort of dialysis patients. METHODS: We screened a large cohort (n = 585) of Italian chronic dialysis patients; from this population, a group of hepatitis B virus surface antigen seronegative patients (n = 213) was tested by Amplicor hepatitis B virus Monitor Test to detect hepatitis B virus viraemia (hepatitis B virus-DNA) in serum. RESULTS: Occult hepatitis B virus infection was absent (zero of 213 = 0%). Persistent hepatitis B virus surface antigen carriage was less frequent than anti-hepatitis B virus core antibody (anti-hepatitis B core antigen) seropositive status in this study group [1.88% (11 of 585) vs. 36% (216 of 585), P = 0.0001]. No dialysis patients seropositive for anti-hepatitis B core antibody in serum (zero of 123 = 0%) had detectable hepatitis B virus-DNA by polymerase chain reaction technology. No significant association between abnormal biochemical liver tests and serum anti-hepatitis B core antibody was noted in our population. Nominal logistic regression analysis demonstrated an independent and significant relationship between anti-HCV antibody and anti-hepatitis B virus core antibody in serum (Wald chi-square 16.06, P = 0.0001). The rate of seropositive patients for anti-hepatitis B virus core antibody was higher among study patients than controls with normal renal function [36.9% (216 of 585) vs. 21.4% (59 of 275), P = 0.0001]; this difference partially persisted after correction for demographic parameters, and viral markers. CONCLUSION: In conclusion, occult hepatitis B virus was absent in our study group. Anti-hepatitis B core antibody was significantly related to presence of anti-HCV antibody supporting shared modes of transmission. Clinical studies based on molecular biology techniques provided with higher sensitivity are planned.     

Effect of anti-viral therapy for occult hepatitis C virus infection

BACKGROUND: Occult hepatitis C virus infection is defined by the presence of hepatitis C virus-RNA in liver but with undetectable anti-hepatitis C virus and serum viral RNA. AIM: To study the response to anti-viral therapy in occult hepatitis C virus infection to assess the pathogenic effect of occult hepatitis C virus. METHODS: Ten patients with occult hepatitis C virus infection were treated with pegylated-interferon plus ribavirin for 24 weeks and were followed-up 24 weeks after therapy. All patients had abnormal alanine aminotransferase, hepatitis C virus-RNA positive in peripheral blood mononuclear cells and liver necroinflammation. RESULTS: At the end of treatment and follow-up, the percentage of patients with normal alanine aminotransferase was 80% (95% CI: 48-96%) and 60% (95% CI: 31-84%) respectively, and hepatitis C virus-RNA in peripheral blood mononuclear cells was negative in 80% (95% CI: 48-96%) and 70% (95% CI: 40-90%) cases. At the end of follow-up sustained response was observed in 30% (95% CI: 11-61%) of cases. Five patients underwent a second liver biopsy. In all cases, liver hepatitis C virus-RNA persisted, although hepatitis C virus-RNA load was significantly lower (3.2 x 10(4) +/- 5.1 x 10(4) copies/microg RNA) than in the basal biopsy (2.4 x 10(5) +/- 3.8 x 10(5) copies/microg RNA); (P = 0.043). Necroinflammation and fibrosis decreased in three cases. CONCLUSION: The biochemical, virological and histological response to therapy achieved in patients with occult hepatitis C virus infection demonstrates the pathologic effects of occult hepatitis C virus.     

Mother-to-child transmission of hepatitis C virus infection

The prevalence of hepatitis C virus (HCV) infection among pregnant women in Europe is generally below 2%. Although women with a history of parenteral exposures or injecting drug use are at an increased risk of infection, a substantial proportion of infected women do not report any risk factors. Targeted screening is thus not recommended. The risk of mother-to-child, or vertical, transmission of HCV is about 5% overall but can be as high as 15%, depending on maternal HIV infection status and HCV RNA viral load. Larger studies are needed to confirm or refute the potential protective effect of elective cesarean section delivery. However, for HCV-positive women who are co-infected with HIV, elective cesarean section delivery is associated with a reduced risk of vertical transmission of HIV as well as HCV. The risk of postnatal transmission through breastfeeding cannot be excluded but is likely to be low for most HCV-infected women. The long-term natural history of vertically acquired HCV needs further elucidation and the efficacy of potential therapies for infected children need to be evaluated in randomized controlled trials.     

Meta-analysis: the impact of diabetes mellitus on the immunological response to hepatitis B virus vaccine in dialysis patients

Aliment Pharmacol Ther 2011; 33: 815–821

Summary

Background Patients on maintenance dialysis typically show a suboptimal immune response to hepatitis B virus vaccine compared with the non‐uraemic population. A variety of inherited or acquired factors have been implicated in this diminished response. It is well known that patients with diabetes mellitus have a compromised immune system, and diabetic nephropathy is an important cause of chronic kidney disease. However, the impact of diabetes mellitus on the immune response to HBV vaccine in patients receiving long‐term dialysis remains unclear. Aim To evaluate the influence of diabetes mellitus on the immune response to HBV vaccine in dialysis population by performing a systematic review of the literature with a meta‐analysis of clinical studies. Methods We used the random effects model of DerSimonian and Laird with heterogeneity and sensitivity analyses. The end‐point of interest was the rate of patients showing seroprotective antibody against hepatitis B surface antigen at completion of vaccine schedule in the diabetic vs. the nondiabetic dialysis individuals. Results We identified 12 studies involving 1002 unique patients on long‐term dialysis. Aggregation of study results showed a significant decrease in response rates among the diabetic vs. the nondiabetic patients [pooled odds ratio = 0.52 (95% CI 0.38–0.71)]. The P‐value was 0.29 for our test of study heterogeneity. Stratified analysis in various subgroups of interest did not meaningfully change our results. Conclusions Our meta‐analysis showed a clear association between diabetes mellitus and impaired response to hepatitis B virus vaccine in individuals on long‐term dialysis. Such a relationship is biologically plausible. Vaccination schedules with adapted vaccine doses and frequent serum testing for loss of immunity against hepatitis B virus should be considered in patients on maintenance dialysis with diabetes mellitus.     

阿片类药物的滥用与丙型肝炎病毒感染

丙型肝炎病毒(hepatitis C virus,HCV)是一种对人类健康危害严重的病原微生物.注射毒品是HCV传播的主要方式.毒品滥用已被认为是HCV感染和疾病发展的协同因素,它显著提高了HCV感染的发病率和死亡率.     

Emerging therapies for hepatitis C virus infection

Hepatitis C virus (HCV) has infected millions of people worldwide and has emerged as a global health crisis. The currently available therapy is interferon (IFN) either alone or in combination with ribavirin. However, the disappointing efficacy of IFN has led to the considerable need for improved treatments and a number of new therapies are under evaluation in clinical trials. These include pegylated IFNs, which have altered physiochemical characteristics allowing once-weekly dosing. Combination of pegylated IFN with ribavirin should further improve sustained response rates. However, not all patients are successfully treated with IFNs, particularly those infected with genotype 1 of the virus, and it is likely that potent, specific drugs will be required. The majority of new approaches currently trying to combat this viral disease are aimed at inhibition of viral targets. Most effort has been directed towards inhibition of the NS3 serine protease, and potent inhibitors have now been described. However, a clinical candidate is yet to emerge against this difficult target. Considerable work by leading researchers has provided crystal structures of the key replicative enzymes, NS3 protease, NS3 helicase, NS5B polymerase and full-length NS3 protease-helicase, and there is much hope that such structural information will bear fruit. More recently, inhibition of host targets, particularly inosine monophosphate dehydrogenase (IMPDH), has become of interest and there are on-going clinical trials with such inhibitors. Research aimed at novel treatments for HCV disease is gathering pace and very recent developments in cell-based assay systems can only hasten the discovery of improved therapies.     

Vedroprevir in the management of hepatitis C virus infection

Introduction: Hepatitis C Virus (HCV) is a chronic infection of the liver and the leading cause of liver failure and liver transplantation worldwide. While prior HCV therapies were prolonged and had variable success rates, the advent of direct-acting antivirals (DAAs) has dramatically improved HCV therapy with minimal side effects, shorter treatment durations, and higher cure rates.

Areas covered: In this paper, we review the literature discussing the use of Vedroprevir (GS-9451) in treatment of HCV in a variety of patient populations. Articles accessible on MEDLINE/PubMed were reviewed to provide context on chemistry, pharmacology, and efficacy of Vedroprevir in HCV treatment.

Expert opinion: Vedroprevir is highly effective in reducing treatment duration in combination with other DAAs without compromising treatment success rates. GS-9451 is insufficient as HCV monotherapy due to low threshold for development of high level of resistance and must be combined with other DAAs to achieve sustained virologic response (SVR).     

Inhibition of hepatitis C virus infection by polyoxometalates

Hepatitis C virus (HCV) infects about 2% of the world population. The standard treatment of chronic HCV infection is still discontented because of the low sustained virological response rate. The development of new HCV antivirals is a healthcare imperative. We explored the potentials of polyoxometalates to inhibit HCV infection using newly developed HCVcc cell culture system. We found one polyoxometalate compound (named POM-12) can inhibit HCV infection at the nanomolar range while displayed little cytotoxicity. We showed that POM-12 inhibited pseudotyped HCV infection but had no effect on HCV RNA replication. Furthermore, we showed that POM-12 was virucidal and can disrupt HCV particles. Finally we demonstrated that POM-12 had no effect on the vesicular stomatitis virus infection while had weak inhibitory activity against the influenza virus infection. In conclusion, we identified a potent anti-HCV compound which may provide an attractive drug candidate to cure HCV infection.     

Management strategies for hepatitis C virus infection in children

Chronic hepatitis C virus (HCV) infection is a major cause of morbidity and mortality worldwide. Progression to cirrhosis and hepatocellular carcinoma occurs in 20% of infected adults. The natural history following childhood infection is less well defined, although cirrhosis in children is described. Since blood product screening for HCV infection was introduced in 1990, most children who acquire HCV do so by vertical transmission from an infected mother. Transmission to offspring occurs in approximately 5%. Most children with HCV infection are asymptomatic. Diagnosis is made by testing those at risk for HCV RNA by polymerase chain reaction (PCR) and HCV antibody (anti-HCV) by enzyme immunoassay (EIA). The clinical impact of HCV infection is assessed by monitoring symptoms and signs, blood testing of liver enzymes, ultrasound imaging, and by liver biopsy. Improved efficacy and tolerability of treatment strategies in adults have had a significant impact on the management of children with HCV infection. The emphasis is now on promoting awareness, early diagnosis, and treatment. Treatment strategies have evolved from monotherapy with interferon alfa (IFNalpha), to combination therapy with ribavirin. Pegylated IFNalpha is superior to conventional IFNalpha, and forms the basis of current recommendations. The genotype of HCV influences treatment efficacy. Treatment is generally well tolerated in children, although adverse effects are common. Preparation and support throughout treatment for the whole family is needed. A proportion of children with HCV infection have co-morbidity, including viral co-infection or hematologic disease. Although treatment may be contraindicated, risks and benefits must be considered before denying treatment. Anemia is more common in those with HIV co-infection, renal insufficiency, thalassemia, or cirrhosis, and may be aggravated by treatment. Children with thalassemia may have iron overload, and transfusion requirements may increase during treatment. Further refinements of combination therapy and development of new drugs are in progress. Vaccine candidates are undergoing phase I and II treatment trials.     

Therapeutic vaccination against chronic hepatitis C virus infection

Approximately 170 million people worldwide are chronic carriers of Hepatitis C virus (HCV). To date, there is no prophylactic vaccine available against HCV. The standard-of-care therapy for HCV infection involves a combination of pegylated interferon-α and ribavirin. This therapy, which is commonly associated with side effects, has a curative rate varying from 43% (HCV genotype 1) to 80% (HCV genotype 2). In 2011, two direct-acting antiviral agents, telaprevir and boceprevir, were approved by the US Food and drug Administration and are now being used in combination with standard-of-care therapy in selected patients infected with HCV genotype 1. Although both drugs are promising, resulting in a shortening of therapy, these drugs also induce additional side effects and have reduced efficacy in patients who did not respond to standard-of-care previously. An alternative approach would be to treat HCV by stimulating the immune system with a therapeutic vaccine ideally aimed at (i) the eradication of HCV-infected cells and (ii) neutralization of infectious HCV particles. The challenge is to develop therapeutic vaccination strategies that are either at least as effective as antiviral drugs but with lower side effects, or vaccines that, when combined with antiviral drugs, can circumvent long-term use of these drugs thereby reducing their side effects. In this review, we summarize and discuss recent preclinical developments in the area of therapeutic vaccination against chronic HCV infection. Although neutralizing antibodies have been described to exert protective immunity, clinical studies on the induction of neutralizing antibodies in therapeutic settings are limited. Therefore, we will primarily discuss therapeutic vaccines which aim to induce effective cellular immune response against HCV.     

Synthetic anti-lipopolysaccharide peptides and hepatitis C virus infection

Introduction: Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and hepatocellular carcinoma. Although antiviral therapy has been markedly improved by the licensing of direct-acting antivirals, safety, resistance, high costs and difficult-to-treat patients remain important challenges.

Areas covered: This article focuses and comments on the recent development of synthetic anti-lipopolysaccharide peptides (SALPs) which bind to highly sulfated glycosaminoglycan/heparan sulfate (HS) on cell surface. HS serves as a primary docking site for several viruses to their respective host cells before the viruses interact with their cell surface receptor(s). In vitro studies have shown that SALPs inhibit entry of HCV without cell toxicity.

Expert opinion: SALPs prevent viral infection in cell culture model systems. Treatment studies of established HCV infection in cell culture models as well as proof-of-concept and safety studies in animal models are needed to evaluate their potential for drug development. The mechanism of action of SALPs as entry inhibitors suggests a potential application for HCV-infected patients to prevent reinfection of the liver graft in liver transplantation. Potential limitations may include high doses to obtain an antiviral effect and a target which is widely expressed and has a key function in cell physiology.     

长期血液透析患者丙型肝炎病毒感染的研究

目的　调查长期血液透析患者丙型肝炎感染状况。方法　用酶联免疫吸附试验 ( EL ISA)法和RT- PCR法检测 13 7例长期血液透析患者血清中的抗丙型肝炎病毒 ( HCV)和丙型肝炎病毒核糖核酸( HCVRNA) ,并且同时检测丙氨酸转氨酶 ( AL T)和天冬氨酸转氨酶 ( AST) ,计算其变动率。结果　 13 7例长期血液透析患者中仅抗 HCV阳性 8例 ,仅 HCVRNA阳性 15例 ,抗 HCV与 HCVRNA同时阳性者 2 4例 ,感染率3 4 .3 %。且透析时间 <2 a的 HCV感染率为 15 % ,透析时间 >2 a以上的其感染率增至 3 7.6%。结论　血透患者中 HCV的感染应引起重视 ,透析的年限越长 ,被 HCV感染的机率就越大。酶学指征的变动率不能作为长期透析患者 HCV感染的敏感指标     

Treatment of early stage chronic hepatitis C virus infection

Introduction: Treatment of Hepatitis C Virus (HCV) with direct acting antivirals (DAAs) is able to achieve the cure of infection in almost the totality of patients, independently of the characteristics of the individual and the virus, using short treatment schedules, and without the need of ribavirin. The high cost of DAAs is the main limiting factor for universal treatment of HCV. However, there is a strong evidence that treatment of infection at the early stage of disease may be the most rewarding approach.

Areas covered: This review evaluates the aspects underlying the benefit of treating chronic HCV infection at the early stage of disease. It outlines the considerations that have to be taken into account when planning treatment in patients with HCV and minimal liver disease, assessing the positive reflex of viral eradication on several HCV-associated extra-hepatic conditions such as the risk of lymphoma, insulin-resistance and glycaemic control, and renal function. Lastly, it also covers the improvement of patients’ quality of life and the pharmaco-economic aspects associated with early treatment.

Expert commentary: Treatment of patients with HCV and minimal liver disease is associated with a beneficial, pleiotropic effect of viral eradication that goes beyond the simplistic consideration of the improvement in liver disease-related outcomes.