Optimal efficacy of ribavirin in the treatment of hepatitis C

A mathematical model to represent hepatitis C is presented. An objective functional keeping biomedical goals in mind is formulated. The optimal control problem is solved numerically to obtain an optimal efficacy of ribavirin in a combination treatment of ribavirin with interferon, where the efficacy of the latter has a clinically validated functional form. Copyright © 2009 John Wiley & Sons, Ltd.     

Acute hepatitis C in patients receiving hemodialysis

Hepatitis C virus (HCV) infection is frequent in patients with end-stage renal disease treated by chronic dialysis, with a prevalence varying from 10-65% according to the geographical data. The prevalence is significantly associated with the duration of dialysis and the number of transfused blood products[1,2] and has dramatically declined with efficient blood screening.[3] We studied patients with acute HCV infection in a dialysis unit. The diagnosis was based on both anti-HCV detection and HCV-RNA detection. Other virological tools including HCV genotype determination was also used to tailor treatment to the individual patient and determine its efficacy for a one-year follow-up period. Seventeen patients (7 male and 10 female, mean age: 63.7 +/- 11.6 SD) with acute hepatitis C were enrolled to our study. All of them were followed up for a period of one year after the diagnosis was established. Phylogenetic analysis distinguished two separate HCV subtypes 1b, which were both responsible for this acute infection (see Figure 1). These types did not differ in their behavior on the clinical situation of our patients, as confirmed by the fact that in both groups of patients, there was only one patient who presented with acute illness. Six patients of our study group, three months after the acute infection, received pegylated interferon (Peg-IFNa2a) 135 mug for a six-month period. Four of them responded very well to therapy and at the first determination HCV RNA was below the cutoff point. One of our patients with very high HCV levels (HCV RNA > 50,000,000 IU/mL), despite receiving the same therapy, did not respond well and developed cirrhosis. In conclusion, it is clear from our experience that better information is needed about the current incidence, prevalence, and risk factors for HCV infection in dialysis patients. Algorithms for the diagnosis and management of hepatitis C should be developed by academic societies. Routine screening for hepatitis C also would allow for better definition of the natural history of hepatitis C in patients with end stage renal disease. [image omitted]Figure 1. NS 5B gene phylogenetic tree analysis of the acute hepatitis C epidemic.     

聚乙二醇化干扰素联合利巴韦林治疗慢性丙型肝炎的疗效及影响因素分析

目的：分析聚乙二醇化干扰素（PegIFN）联合利巴韦林治疗对慢性丙型肝炎的疗效及影响因素。方法使用聚PegIFNα-2a（派罗欣180μg/周）联合利巴韦林（根据体重900～1200 mg/d）治疗60例慢性丙型肝炎患者,疗程48周。结果本研究60例慢性丙型肝炎患者中,HCV-Ⅰ型45例,占75%,非HCV-Ⅰ型15例,占25%。HCV-Ⅰ型和非HCV-Ⅰ型患者持续应答（SVR）率分别为60.0%和93.3%,差异具有统计学意义（χ2=6.162,P=0.013）;基线病毒载量,以HCV RNA定量1＆#215;106 IU/ml划分,HCV RNA高水平组和低水平组SVR分别为48.3%和77.3%,差异具有统计学意义（χ2=6.093,P=0.014）。治疗过程中获得快速病毒学应答（RVR）的病例获得SVR和未获得RVR的病例获得SVR的比率分别为84.6%和38.1%,差异具有统计学意义（χ2=9.690,P=0.002）。治疗过程中获得早期病毒学应答（EVR）的病例获得SVR和未获得EVR的病例获得SVR的比率分别为78.4%和11.1%,差异具有统计学意义（χ2=4.036,P=0.045）。结论慢性丙型肝炎患者的治疗过程中,病毒基因型、基线病毒载量以及治疗过程中是否获得RVR/EVR均可能影响治疗后的持续病毒学应答。     

Hand contamination with hepatitis C virus in staff looking after hepatitis C-positive hemodialysis patients

BACKGROUND: Hepatitis C virus (HCV) is a major cause of hepatitis in hemodialysis (HD) patients. Routes other than blood transfusion play a role in the spread of HCV in HD patients. Molecular studies of HCV implicate nosocomial transmission of the virus in HD units. We conducted a clinicovirological study in our HD unit to investigate if the hands of dialysis personnel could represent a mode of transmission of HCV among HD patients. METHODS: One liter of sterile water was used for each handwashing of dialysis personnel. The washing was collected in a sterile container and tested for HCV-RNA by polymerase chain reaction (PCR) within 3 h of collection. Eighty handwashings from nurses dialyzing HCV-positive patients (groupe A) and 100 handwashing from nurses dialyzing HCV-negative patients (group B) were tested for HCV-RNA. As a control, 60 handwashings were collected from the dialysis personnel before entering the dialysis unit (group C) and tested for HCV-RNA. RESULTS: HCV-RNA was positive in 19 (23.75%) of samples of group A, in 8 (8%) of samples of group B (p < 0.003) and in 2 (3.3%) of samples of group C (p < 0. 35). These two positive samples of group C were from nurses who had dialyzed HCV-negative patients. CONCLUSION: These results indicate the presence of HCV-RNA on the hands of some dialysis personnel in our HD unit, in spite fo adherence to the standard precautions. The hands of dialysis personnel are therefore a potential mode for facilitating transmission of HCV between HD patients.     

维持性血液透析患者感染乙型和丙型肝炎的分析

目的为了评价血液透析（血透）患者乙型和丙型肝炎（HBV、HCV）感染状态及对临床情况和肝功能的影响。方法对62例血透患者应用ELISA法和RT-PCR法检测抗-HCV和HCVRNA，采用斑点杂交法和固相放免法检测HBV标志，并检测肝功能和血浆蛋白电泳。结果62例患者中，抗-HCVIgM阳性27例（43．6％），抗-HCVIgG阳性29例（46．8％），HCVRNA阳性34例（54．8％），三项任一项阳性37例（59．7％），5例（8．1％）HBsAg阳性，其中HBeAg和HBVDNA阳性3例。结论向透患者中HCV感染严重，临床情况及预后差，检测血浆蛋白和电泳较肝功能酶学能更好地作为肝炎诊断和反映病情的指标。     

Elevation of blood thioredoxin in hemodialysis patients with hepatitis C virus infection

BACKGROUND: Thioredoxin (TRX) is a stress-inducible thiol-containing protein, which has been shown to be an indicator of oxidative stress in a variety of diseases. The association between oxidative stress and hepatitis C virus (HCV) infection, however, remains unknown in hemodialysis patients. METHODS: We measured serum TRX levels in 85 hemodialysis patients positive for anti-HCV antibodies (age, 60 +/- 1 years old; hemodialysis duration, 17 +/- 1 years; M/F = 57/28) by enzyme-linked immunosorbent assay (ELISA), and examined whether blood TRX may be associated with HCV-related hepatic injury. RESULTS: Serum TRX was significantly higher in hemodialysis patients with HCV infection (112.3 +/- 3.7 ng/mL, N = 85) than in those without HCV infection (69.7 +/- 3.3 ng/mL, N = 59) (age, 69 +/- 2 years old; hemodialysis duration, 6 +/- 1 years; M/F = 32/27, P < 0.01) or normal subjects (28.0 +/- 5.4 ng/mL, N = 9). TRX was significantly correlated with time on hemodialysis (r = 0.27, P = 0.01) in HCV-positive patients, while it was associated with the patient's age in HCV-negative patients (r = 0.42, P < 0.01). Blood TRX was significantly correlated with asparate aminotransferase in patients with HCV infection (r = 0.34, P < 0.01) and without HCV infection (r = 0.46, P < 0.01). However, serum TRX was not associated with blood alanine aminotransferase, a relatively specific marker of hepatic cellular damage, in HCV-infected hemodialysis patients. A significant relationship was found between serum ferritin and TRX (r = 0.25, P = 0.02) and malondialdehyde (MDA) values (r = 0.25, P = 002) in HCV-positive patients. Serum TRX was also higher in the patients receiving weekly iron supplement with HCV infection (135.3 +/- 10.2 ng/mL vs. 110.2 +/- 3.9 ng/mL, P = 0.06) and without HCV infection (91.8 +/- 12.1 ng/mL vs. 65.2 +/- 2.7 ng/mL, P < 0.01). CONCLUSION: There was a greater increase in serum TRX in hemodialysis patients with HCV viremia than without HCV viremia. However, there may not be an association between serum TRX and HCV-related hepatic injury. TRX increased with serum ferritin in HCV-infected patients and further increased by iron infusion. These findings indicate that HCV infection and iron loading may aggravate oxidative stress in dialysis patients.     

Oxidative stress markers in hepatitis C infected hemodialysis patients

BACKGROUND: Oxidative stress in hemodialysis (HD) patients or hepatitis C virus (HCV) infections may be related to increased production of free radicals. We assessed the effect of HCV infection on the oxidative stress markers, malondialdehyde (as TBARS), protein carbonyl content and protein sulfhydryl groups, in chronic HD patients. METHODS: Twenty HCV infected patients (9 men and 11 women, age 44.8 +/- 14.3 years) and 10 non-HCV infected patients (6 men and 4 women, age 55.6 +/- 14.3 years) receiving regular HD were recruited. The average hemodialysis duration was 30 +/- 8 months for HCV (+) patients and 14 +/- 8 months for HCV (-) patients. Controls consisted of healthy subjects. RESULTS: Serum TBARS and carbonyl content were significantly elevated in HCV(-) patients (p<0.001, p<0.05) and in HCV(+) patients (p<0.001, p<0.001) vs. Controls. There was also a significant difference in serum TBARS and carbonyl content between HCV(-) patients and HCV(+) patients (p<0.001, p<0.05). Serum protein sulfhydryl groups in HCV(-) and HCV(+) patients were the same, but significantly lower than in Controls (p<0.001, p<0.001). When HCV(+) patients were divided into two sub-groups, one with shorter (13.4 +/- 8 months; n=7) and the other with longer (40.3 +/- 8 months; n=13) duration of HD treatment, no differences were found between subgroups. CONCLUSION: HCV infection may aggravate oxidative stress in HD patients.     

Outcome of treatment with pegylated interferon and ribavirin in heart transplant recipients with chronic hepatitis C

Background/aim

The combination of pegylated interferon (PEG-IFN) and ribavirin (RBV) is the current treatment for chronic hepatitis C (CHC). The treatment is thought to suppress viral replication and induce viral clearance via immunomodulatory effects. For this reason, concern exists for the use of this treatment in recipients of a solid organ transplantation. We sought to evaluate the safety and efficacy of PEG-IFN/RBV in heart transplant recipients with CHC.

Methods

From June 2005 to September 2009, we treated three CHC patients with heart transplantation. PEG-IFN alpha2b and RBV doses and treatment duration were set according to the hepatitis C virus (HCV) genotype and body weight as per current recommendations. Dose reductions were dictated by individual patient tolerability. Cardiac safety was monitored by clinical examinations, echocardiography, and measurement of troponin I and B-type natriuretic peptide, as well as endomyocardial biopsies.

Results

All three patients, displayed HCV genotype 1b infection, viral loads of >5 logs, and a Scheuer fibrosis score ≥ 2. Two of them completed the prescribed treatment course becoming sustained virological responders. The other patient had an initial complete virological response, but subsequently experienced a viral breakthrough after reduction of PEG-IFN and withdrawal of RBV due to severe anemia. We observed no cardiovascular adverse events nor rejection episodes. Posttreatment clinical history and examination, electrocardiography, and echocardiography did not show any sign of graft dysfunction.

Conclusions

Treatment with PEG-IFN/RBV may be safely offered to stable heart transplant recipients with CHC and signs of liver disease progression. Close monitoring of treatment safety is mandatory.     

Occult hepatitis C virus infection among hemodialysis patients

Occult hepatitis C virus (HCV) infection (i.e., detectable HCV-RNA in the liver or peripheral blood mononuclear cells) in the absence of both serum HCV-RNA and anti-HCV antibodies has not been investigated in hemodialysis patients. In this study, real-time PCR and in situ hybridization was used to test for the presence of genomic and antigenomic HCV-RNA in peripheral blood mononuclear cells of 109 hemodialysis patients with abnormal levels of liver enzymes. Occult HCV infection, determined by the presence of genomic HCV-RNA, was found in 45% of the patients; 53% of these patients had ongoing HCV replication, indicated by the presence of antigenomic HCV-RNA. Patients with occult HCV infection had spent a significantly longer time on hemodialysis and had significantly higher mean alanine aminotransferase levels during the 6 mo before study entry. Logistic regression analysis revealed that mortality was associated with age >60 yr (odds ratio 3.30; 95% confidence interval 1.05 to 10.33) and the presence of occult HCV infection (odds ratio 3.84; 95% confidence interval 1.29 to 11.43). In conclusion, the prevalence of occult HCV infection is high among hemodialysis patients with persistently abnormal values of liver enzymes of unknown cause. The clinical significance of occult HCV infection in these patients requires further study.     

维持性血液透析患者丙肝病毒感染预后分析

目的 探讨丙肝病毒感染对维持性血液透析患者预后的影响.方法 对106例死亡的维持性血液透析患者按丙肝阳性和丙肝阴性分组进行回顾性分析.结果 两组年龄、性别、原发病、肾功能、血糖、血脂、Hb、 Kt/V无统计学差异.阳性组出现肝酶升高、血白蛋白降低,较阴性组有显著性差异.阳性组透析龄59个月较阴性组85个月明显缩短,心血管事件为两组最常见死亡原因.结论 丙肝病毒感染维持性血液透析患者肝功能异常,生存时间缩短.     

Leukopenia and thrombocytopenia in hemodialysis patients with hepatitis B or C virus infection and non-hemodialysis patients with hepatitis cirrhosis

AIMS: To investigate the relation of leukopenia and thrombocytopenia in hemodialysis (HD) patients with hepatitis C virus (HCV) infection. MATERIALS AND METHODS: The study included 86 HD patients with hepatitis B surface antigen-negative and hepatitis C antibody-negative, 28 HD patients with hepatitis C antibody-positive, 22 HD patients with hepatitis B surface antigen-positive, 78 non-HD patients with hepatitis B-induced liver cirrhosis and 38 non-hemodialysis patients with hepatitis C-induced liver cirrhosis. The following parameters were checked: anti-HCV, hepatitis B surface antigen, hemoglobin, hematocrit, white blood cells, platelets, calcium, phosphate, iron, ferritin, albumin, globulin, aspartate transaminase (AST), alanine transaminase (ALT) and C-reactive protein. The history of blood transfusions, medications, erythropoietin doses and adequate dialysis (KTNV) for 6 consecutive months was also recorded from charts. RESULTS: The HD patients with positive serum anti-HCV and non-HD patients with hepatitis B- or C-induced liver cirrhosis had higher prevalences of leukopenia (39.3%, 43.6% and 50% vs. 15.1%; p < 0.001) and thrombocytopenia (67.9%, 89.7% and 81.6% vs. 34.9%: p < 0.001) than HD patients with serum anti-HCV(-)HbsAg(-). The WBC (4,432 +/- 1,394, 4,792 +/- 2,263 and 4,624 2,446 vs. 5,590 +/- 1,500/mm3; p < 0.001) and platelet counts (140 +/- 45, 80 +/- 50 and 89 +/- 65 vs. 186 +/- 62 x 10(3)/mm3; p < 0.001) of HD patients with positive serum anti-HCV and non-HD patients with hepatitis B- or C-induced cirrhosis were also lower than HD patients without anti-HCV antibody. The liver cirrhosis patients had more thrombocytopenia than the HD patients with anti-HCV(+). The WBC and platelet counts did not vary between HD patients with HbsAg(+) and HD patients with anti-HCV(-)HBsAg(-). The durations of HD, hepatitis and liver cirrhosis were not related to the leukopenia or thrombocytopenia (p > 0.05). CONCLUSIONS: HCV infection associated with leukopenia and/or thrombocytopenia in HD patients is as common as in non-HD patients with liver cirrhosis. This may be due to the direct effect of hemopoiesis rather than the hyperspleenism of liver cirrhosis patients. There is a need for further prospective investigation to ascertain the clinical significance of leukopenia and thrombocytopenia in HD patients with anti-HCV(+). The prevalence of leukopenia and thrombocytopenia was higher in HD patients with hepatitis C than in HD patients with hepatitis B and HD patient without hepatitis.