Symptomatic and Virological Response to Antiviral Therapy in Hepatitis C Associated with Extrahepatic Complications of Cryoglobulimia

Mixed cryoglobulins are detected in 50% of patients with hepatitis C; fortunately, few have vasculitis affecting skin, peripheral nerves, kidneys, and synovia. This study was designed to identify the natural history of symptomatic cryoglobulinemia and evaluate the response to antiviral therapy. Patients with hepatitis C complicated by symptomatic cryoglobulinemia were assessed for their disease manifestations and response to antiviral therapy. Of 83 patients identified, 56 patients with a minimum of 12 months follow-up were reviewed. Manifestations included dermatologic (75%), rheumatologic (57%), neurologic (34%), and renal (proteinuria 25%). Antiviral therapy was given to 38, of whom 9 were retreated for symptomatic and/or virological nonresponse. Antiviral therapy included interferon monotherapy (n= 8), pegylated-interferon monotherapy (n= 5), consensus-interferon (n= 2), interferon + ribavirin (n= 18), and pegylated-interferon + ribavirin (n= 14). Treatment provided sustained symptomatic response in 31 (82%) and virological response in 16 (42%) patients. Symptomatic cryoglobulinemia responds well to antiviral therapy, even when virological response is not achieved.     

Baseline High Viral Load and Unfavorable Patterns of Alanine Aminotransferase Change Predict Virological Relapse in Patients With Chronic Hepatitis C Genotype 1 or 2 Obtaining Rapid Virological Response During Antiviral Therapy

Background

Rapid virological response (RVR) strongly predicts sustained virological response (SVR) in patients with chronic hepatitis C (CHC), and abbreviates antiviral therapy in some patients.

Objectives

To identify factors predicting virological relapse (VR) in CHC patients who attained RVR.

Patients and Methods

Medical records of 133 CHC patients with an RVR after completing 24 weeks of antiviral therapy (a combination of pegylated interferon-α and ribavirin) were analyzed. Baseline characteristics and on-treatment responses were compared between the patients with an SVR and those with VR. Patients with normal alanine aminotransferase (ALT) levels at weeks 4 and 12 and at the end-of-treatment (EoT) and patients with elevated, but constantly decreasing, ALT levels were classified as having favorable patterns of ALT change. A trend of increasing ALT levels either between weeks 4 and 12 or between weeks 12 and EoT was classified as unfavorable. A high viral load (HVL) was defined as a baseline HCV RNA ≥ 600000 IU/mL.

Results

In total, 116 (87.2%) patients had a SVR and 14 (10.5%) had VR. The VR rates were comparable between patients with genotype-1 (13.1%) and genotype-2 infection (8.7%) (P = 0.572). Multivariate analysis revealed that HVL (P = 0.015; odds ratio [OR] = 14.754; 95% confidence interval (CI) = 1.671–130.240), and unfavorable ALT patterns (P = 0.039; OR = 4.397; 95% CI = 1.078–17.930) independently predicted VR. In subgroup analysis, low viral load (LVL) patients had a minimal VR rate (1.8%). Among the HVL patients, the VR rate of those using peg-IFN-α-2a was relatively low (9.1%). Patients using peg-IFN-α-2b had a slightly higher VR rate (23.8%; P = 0.128), and patients with favorable patterns of ALT changes had a lower VR rate (10.3%) compared to the 53.8% in patients with unfavorable ALT patterns (P = 0.005).

Conclusions

In southern Taiwan, 24 weeks of antiviral therapy achieved a high SVR rate in patients with CHC attaining RVR, except in the subgroup of patients treated with peg-IFN-α-2b with HVL and on-treatment unfavorable ALT patterns.     

Sustained Virological Response in Chronic Hepatitis C Patients after a 6- and a 36-Month Interferon-a2b Treatment Schedule. A Multicenter,Randomized, Controlled Study

With the introduction of medical treatment (chenodeoxycholic acid therapy) of cholesterol gallstones, the prediction of the gallstone type, cholesterol — non-cholesterol stones (i.e. cholesterol predominating or not), has become important. In 24 consecutive patients admitted for surgery because of gallstones, the value of various criteria for differentiation between the two types of stones was assessed. It is concluded that the combined requirements of radiolucency of the stones and a cholesterol saturation index in duodenal bile above 1.00 constitutes a fairly reliable method for selection of patients for dissolution therapy with chenodeoxycholic acid.     

重视乙型肝炎相关肝硬化的抗病毒治疗

全世界每年有100万乙型肝炎病毒感染者死于其相关的肝硬化和肝癌,慢性乙型肝炎患者5年内有6％～20％开展至肝硬化,慢性乙型肝炎肝硬化的发生率、病情进展以及预后与血清HBVDNA水平密切相关,因此,对乙型肝炎相关肝硬化抗病毒治疗非常重要,需要引起足够的重视。     

Real Response to Therapy in Chronic Hepatitis C Virus Patients: A Study From Iran

Background

Despite significant advances in the treatment of chronic hepatitis C in the past decades, factors which can affect response rates to combination therapy; peginterferon and ribavirin, are still under study and reaching sustained virological response (SVR) is affected by several different factors.

Objectives

To investigate predictor factors contributing to SVR in Iranian patients.

Patients and Methods

The present non-randomized, clinical trial was conducted on 100 patients referred to the Tehran Hepatitis Center in 2009-2011. The patients were administered combined peginterferon α-2a-ribavirin treatment, based on the standard protocol of the Iranian Ministry of Health. At the end of the treatment, the SVR rate and predictors were evaluated.

Results

The mean age of the patients was 42 and 78% were male. Genotype 1a was the most common (70%) and 55% of patients were treatment naïve. The outcomes showed that 12%, 16% and 22% patients were; non-responders, breakthroughs and relapsers, respectively, while 50% of the patients reached SVR. Patients reaching SVR were aged 40 years or lower, they were less likely to have been a non-responder in prior treatments, more likely to have a non-1a genotype and a higher number had an HCV RNA of less than 600 000 IU/ml. The multivariate analysis showed that an age of 40 or lower (OR = 3.74, CI95% = 1.52-9.22), a non-1a genotype (OR = 3.71, CI 95% = 1.40-9.81) and an HCV RNA less than 600 000 IU/ml (OR = 2.52, CI 95% = 1.03-6.15) may be useful SVR predictors.

Conclusions

The findings of the present study showed that half of the patients reached SVR through combined peginterferon α-2a and ribavirin treatment, the majority of whom had genotype 3a and a minority had genotype 1a. In addition, an age of 40 or lower, non-1a genotype and a viral load less than 600 000 IU/ml were strong SVR predictors.     

慢性乙型肝炎患者抗病毒治疗早期T细胞表面PD-1的表达

背景：慢性乙型肝炎病毒（HBV）感染者T细胞表面程序性死亡受体1（PD-1）呈持续性高表达。然而关于抗病毒治疗前后慢性乙型肝炎（CHB）患者T细胞表面PD-1表达变化及其与病毒载量关系的报道较少。目的：动态观察CHB患者抗病毒治疗早期外周血CD4＋和CD8＋T细胞表面PD-1表达水平,探讨其表达与血清HBV DNA载量和丙氨酸氨基转移酶（ALT）水平之间的关系。方法：以流式细胞术分别检测31例CHB患者抗病毒治疗前或基线期（T1）、治疗后4～8周（他）和12．16周（T3）的外周血CD4^＋和CD8^＋T细胞表面PD-1表达水平,以实时荧光定量聚合酶链反应（PCR）检测血清HBV DNA载量,同时检测血清ALT水平。结果：抗病毒治疗早期,CHB患者外周血CD4^＋和CD8^＋T细胞表面PD．1表达水平逐渐下调（P〈0．05）,血清HBV DNA载量和ALT水平亦逐步降低（P〈0．01）;CD4^＋和CD8^＋T细胞表面PD-1表达与HBV DNA载量（P〈0．01）和ALT水平（P〈0．05）均呈正相关。结论：有效的抗病毒治疗可通过降低CHB患者的病毒载量使T细胞表面PD-1表达下调,T细胞表面PD-1表达水平与患者疾病状态密切相关。     

长期服用联苯双酯治疗慢性乙型肝炎的病毒学疗效探讨

目的:探讨慢性乙型肝炎患者长期口服联苯双酯的抗病毒作用及安全性,为慢性乙型肝炎的抗病毒治疗寻找一种有效而廉价的药物。方法:患者96例,其中男68例,女28例,平均年龄27.93岁(13～65岁),联苯双酯45.O～67.5mg/d,分3次口服,疗程12个月以上。观察患者的生化反应和病毒学反应。结果:经联苯双酯治疗后患者血清丙氨酸转氨酶(ALT)均迅速降低,1月后ALT恢复正常者72.92％。血清HBeAg阴转率和HBV DNA阴转率均随疗程的延长而逐渐升高,治疗30个月时HBeAg 阴转率达47.5％.HBV DNA阴转率达35.42％。未见明显毒副作用。结论:长期服用联苯双酯不但具有良好的降酶作用,尚具有良好的抗乙肝病毒作用。     

A Comprehensive Long-Term Prognosis of Chronic Hepatitis C Patients With Antiviral Therapy: A Meta-Analysis of Studies From 2008 to 2014

Context:

Attaining a sustained virological response with antiviral therapy is a sign of clinical cure for chronic hepatitis C patients. The aim of this meta-analysis was to evaluate the long-term efficiency and outcome of antiviral therapy in patients with hepatitis C who attained a sustained virological response.

Evidence Acquisition:

A literature search was performed on published articles between January 2008 and February 2014. Patients with Hepatitis C who received interferon with or without ribavirin therapy were enrolled. Relative risks were estimated using either fixed or random effect models.

Results:

Patients who attained sustained virological response had a less risk (85%) for all-cause mortality and about 63% reduced risk of hepatocellular carcinoma incidence than those who did not achieve sustained virological response. Based on deeply analysis, the stage of liver fibrosis was a risk factor at baseline for the incidence of hepatocellular carcinoma.

Conclusions:

Sustained virological response can reduce all-cause mortality and the incidence of hepatocellular carcinoma of patients with hepatitis C. Advanced liver fibrosis is still a risk factor for the incidence of hepatocellular carcinoma, in spite of hepatitis C patients attained a sustained virological response.     

Circulating IL-2 and IL-10 in Chronic Active Hepatitis C with Respect to the Response to IFN Treatment

Summary Background: The importance of circulating immunoregulatory cytokines in response to IFN treatment and the change of in vivo production of these cytokines during interferion (IFN) treatment are not well known. We aimed to determine whether pretreatment serum levels of IL-2 and IL-10 are predictive of the response to IFN treatment and to investigate if treatment response or nonresponse has any effect on the circulating levels of these cytokines. Patients and Methods: 37 patients (18 responders and 19 non-responders) with chronic hepatitis C virus (HCV) infection who received IFN-α2b for 6 months were studied. Responders were defined by complete alanine aminotransferase (ALT) normalization and loss of HCV RNA as detected by bDNA assay while patients who had elevated ALT levels and positive HCV RNA after 6 months were considered as nonresponders. Results: Genotype distribution, ALT and HCG RNA levels were similar in responders and nonresponders. A significant number of patients with chronic hepatitis C (20/37 = 54%) had elevated IL-2 levels while IL-10 levels were not different from controls. No difference in baseline cytokine levels was observed between responders and non-responders. In the posttreatment serum samples some patients lost their detectable IL-2 or IL-10; some patients developed detectable cytokine levels after treatment irrespective of the treatment response. Conclusion: These results suggest that active liver injury in chronic hepatitis C is associated with increased circulating Th1 cytokine IL-2 but not with Th2 cytokine IL-10 and that circulating levels of these cytokines do not predict the response to IFN treatment. There is no constant and regular change in circulating levels of these cytokines under IFN treatment with respect to treatment response. Received: June 6, 2000 · Revision accepted: July 21, 2000     

The Safety of The Directly Acting Antiviral Treatment For Hepatitis C Virus According To The Egyptian National Program Protocol In Patients With Midrange Ejection Fraction

Background:The Egyptian National Committee of Viral Hepatitis program is the leading national hepatitis C virus (HCV) management program globally. However, limited data is available about the effect of the new directly acting antiviral agents on the cardiovascular system.Objectives:Our study aimed to assess the safety of the relatively new directly acting antiviral agents approved by the National Health Committee in Egypt to treat patients infected with hepatitis C virus who have midrange left ventricular ejection fraction.Methods:This multicenter study included 400 successive patients with an ejection fraction (40–49%) from May 2017 to December 2019. We classified them into two groups: Group I (Child A), who received Sofosbuvir and Daclatasvir for twelve weeks, and Group II (Child B), who received Sofosbuvir, Daclatasvir, and Ribavirin for twelve weeks. Patients were evaluated for their symptoms, ejection fraction, brain natriuretic peptide, lipid profile, fasting blood glucose, fasting insulin, Homeostatic Model Assessment of Insulin Resistance levels, and Holter monitoring (just before the start of treatment and within three days after completing therapy).Results:We found New York Heart Association Class, ejection fraction, brain natriuretic peptide, premature ventricular contractions burden, as well as highest and lowest heart rate did not show a statistically significant difference in both groups after treatment. The treatment did not cause bradycardia or non-sustained ventricular tachycardia. Fasting blood glucose and fasting insulin levels declined, with improved insulin resistance after treatment in both groups. Both low and high-density lipoprotein cholesterol increased after treatment in Group II.Conclusions:Both regimens of directly acting antiviral agents used in Egypt to treat chronic hepatitis C virus infection are safe in patients with New York Heart Association Class I and II with midrange left ventricular ejection fraction (40–49%). There are beneficial metabolic changes following HCV clearance as an improvement of insulin resistance.     

Predictors of Pegylated Interferon Alpha and Ribavirin Efficacy and Long-Term Assessment of Relapse in Patients With Chronic Hepatitis C: A One-Center Experience From China

Background:

Sustained virological response (SVR) and virological relapse maintain pivotal roles in the management of chronic hepatitis C (CHC); however, there is little data regarding the long-term outcomes of patients with CHC in China.

Objectives:

We aimed to investigate the predictive factors of therapeutic effect and viral relapse in patients who achieved end-of-treatment response (ETR).

Patients and Methods:

We retrospectively analyzed clinical, biochemical and virological data of 169 adult patients with CHC from China who were not treated with pegylated interferon-alpha (PEG IFN-α) and ribavirin, of which 142 achieved ETR and with a follow-up period ranging from six months to six years. Statistical analysis was performed by SPSS 20.0.

Results:

Of the 169 patients, 124 (73.4%) achieved SVR and 23 (16.2%) experienced relapses post-therapy in cases of ETR patients. We considered sex, age, alanine aminotransferase, aspartate transaminase, baseline hepatitis C virus RNA level, HCV genotypes, IL28B rs12979860 genotype, rapid virological response (RVR), and early virological response (EVR). For antiviral effect in patients with CHC, HCV genotypes (2, 3) (χ² = 11.285, P = 0.001), IL28B genotype (rs12979860 CC) (χ² = 16.552, P < 0.001), RVR (χ² = 37.339, P < 0.001), and EVR (χ² = 70.265, P < 0.001) were significantly correlated with achieving SVR. For ETR patients with long-term follow-up, the relapse rate within six months was significantly higher than within other periods during six-year follow-up (χ² = 7.792, P = 0.005). Relapse was virtually not observed after therapy ceased for 48 weeks. The IL28B genotype (rs12979860 CT/TT) (OR = 0.102; 95% CI, 0.031-0.339; P < 0.001), lower RVR (OR = 0.239; 95% CI, 0.078-0.738; P = 0.013), and EVR (OR = 0.102; 95% CI, 0.016-0.661; P = 0.017) were independent risk factors for relapse.

Conclusions:

Our study comprehensively explored the predictive factors of therapeutic effect of administered drugs and analyzed viral relapse during a six-months to six-year follow-up period from China. The SVR may not be the perfect endpoint of HCV therapy in Chinese people; we recommend 48 weeks after treatment withdrawal as the suitable time point.     

Interferon Beta 1a versus Interferon Beta 1a plus Ribavirin for the Treatment of Chronic Hepatitis C in Chinese Patients: A Randomized, Placebo-Controlled Trial

For chronic hepatitis C virus (HCV) infection, the effects of current therapies are limited. To evaluate the efficacy and safety of the interferon beta-1a (IFN β-1a) versus IFN β-1a plus ribavirin (RBV) combination on Chinese treatment-naïve patients with chronic hepatitis C, a randomized, placebo-controlled study was performed. A total of 26 naïve patients histologically confirmed to have chronic hepatitis C were double-blindly and randomly assigned to receive either IFN β-1a 44 μg (12 MIU) (IFN β-1a group) or placebo (placebo group) three times per week for 12 weeks. At the end of the 12 weeks of treatment, the patients who received IFN β-1a continued to complete 24 weeks of treatment. Placebo non-responders were crossed over to IFN β-1a plus RBV (1,000–1,200 mg/day) combination therapy (IFN β-1a plus RBV group) for 24 weeks after 4 weeks washout. All patients were followed up for 24 weeks after the end of treatment. Sustained virological response (SVR) was defined as the absence of detectable HCV RNA in the serum both at the end of 24 weeks of treatment and at the end of 24 weeks of untreated follow-up. There were no differences in the clinical background between the groups before the initiation of treatment. At the end of the 12 weeks of double-blind therapy, HCV RNA was negative and undetectable in 10/11 patients (90.9%) in the IFN β-1a group and none in the placebo group. The virological response rate (14/15, 93.3%) of the IFN β-1a plus RBV group at week 12 after the initiation of therapy was similar to that of the IFN β-1a group. SVR was observed in 5/11 (45.5%) of the IFN β-1a group and 11/15 (73.3%) of the IFN β-1a plus RBV group (P = 0.23). At the end of follow-up, a biochemical response was found in 5/11 patients in the IFN β-1a group (45.5%) and 8/15 patients in the IFN β-1a plus RBV group (53.3%, P = 1.00). Multiple logistic regression analysis confirmed that an HCV RNA load lower than 1.0×10⁶ copies/ml was independently associated with SVR (OR 11.00; 95% CI 1.81–66.97; P = 0.003). The side effects were mild and similar in the two therapy groups. We conclude that IFN β-1a alone or in combination with RBV provided considerable benefit in Chinese naïve patients with chronic hepatitis C. Treatments with IFN β-1a alone or IFN β-1a plus RBV are safe and well tolerated, and may represent an alternative for chronic hepatitis C patients who are unable to tolerate pegylated interferon α.     

真实世界中不同ALT、AST水平慢性丙型肝炎患者对直接抗病毒药物治疗的病毒学应答及肝纤维化指标变化情况

目的探讨真实世界中不同ALT、AST水平的慢性丙型肝炎患者对直接抗病毒药物(DAA)治疗的病毒学应答,以及治疗后肝硬度测定(LSM)值、4项因素的肝纤维化指数(FIB-4)和AST/PLT比值指数(APRI)的变化情况。方法纳入2017年12月—2020年5月在北京大学第一医院感染疾病科门诊就诊的慢性丙型肝炎患者,计算患者治疗病毒学应答率。采用Wilcoxon秩和检验对比不同组间基线及治疗结束第12周LSM、FIB-4和APRI的变化;计数资料组间比较采用χ2检验。结果共纳入48例慢性丙型肝炎患者,其中基线ALT或AST出现异常的患者为33.3%。所有患者DAA治疗第4周病毒学应答率为85.4%,治疗结束时、治疗结束12、24、48周均为100%;治疗结束第12周较基线LSM[6.1(5.1~12.4)kPa vs 8.6(5.7~16.9)kPa,Z=-1.676,P=0.043]、APRI[0.24(0.19~0.48)vs 0.42(0.23~1.17),Z=-2.050,P=0.027]差异有统计学意义。ALT或AST异常的患者治疗结束12周与基线LSM[8.9(5.6~13.1)kPa vs 14.4(8.0~28.2)kPa,Z=-1.679,P=0.047]、APRI[0.44(0.25~0.50)vs 1.29(0.99~2.09),Z=-3.427,P=0.001]差异有统计学意义。结论慢性丙型肝炎患者DAA治疗后持续病毒学应答率高,基线ALT或AST有异常较无异常的患者在治疗后LSM及APRI改善更明显。     

延长利巴韦林疗程后获持续病毒学应答的丙型肝炎患者1例

一、病例资料女性患者,57岁,汉族,辽宁籍,公务员.2008年4月,患者体检时发现丙型肝炎抗体阳性,但肝功能正常,未予诊治.患者既往有脂肪肝,但未行特殊治疗.     

Amino Acid Polymorphisms Within the Entire HCV NS5A Region in Estonian Chronic HCV 1b Patients With Different Treatment Response

Background

A substantial proportion of hepatitis C virus (HCV)-1b infected patients do not response to pegylated interferon-α plus ribavirin (PegIFNα/RBV) combination therapy that was partially associated with mutations in the non-structural 5A (NS5A) protein.

Objectives

Analysis of NS5A polymorphisms in HCV genotype 1b pre-treatment serum samples from Estonian patients and their effect on the treatment response.

Patients and Methods

Twenty-nine complete NS5A sequences obtained from patients with chronic HCV-1b infection who had received combined therapy with PegIFNα-2a/RBV were analyzed and compared with the prototype strain HCV-J. Twelve patients achieved a sustained virological response (SVR), 15 were non-SVR and 2 patients stopped treatment because of side effects.

Results

No significant difference in total number of amino acid mutations was observed between isolates from SVR and non-SVR patients in any known regions of the NS5A protein. However, specific amino acid substitutions at positions 1989 and 2283 correlated significantly with SVR, mutations at positions 1979, 2107, 2171 and 2382 were associated with non-response to treatment and amino acid substitution at position 2319 was observed in relapsers. At phylogenetic analysis, NS5A nucleotide sequences have been subdivided into four groups characterized by the different treatment response. Twenty-four novel nucleotide polymorphisms and 11 novel amino acid polymorphisms were identified based on the phylogenetic tree topology.

Conclusions

Specific amino acid substitutions correlating with the treatment response were found. Polymorphisms revealed by phylogenetic analysis may define the signature patterns for treatment susceptible and treatment resistant strains prevalent in Estonia.     

复合α干扰素联合病毒唑治疗慢性丙型肝炎的临床研究

目的：观察复合α干扰素（CIFN）联合病毒唑治疗慢性丙型肝炎的临床效果及用药安全性,探讨临床抗慢性丙型肝炎病毒的方法。方法：选择68例慢性丙型肝炎患者并随机分成联合治疗组与对照组,联合治疗组38例,给予CIFN15μg,隔日皮下注射,加病毒唑450mg.tid口服,疗程为6个月,对照组30例,单用干扰素α-2b,3MU,隔日肌注1次,疗程6个月;两组停药后随访6个月。观察两组治疗前后的临床症状,体征改善状况,生化应答率,病毒应答率和临床副作用。结果：疗程结束时联合治疗组临床症状,体征的缓解率为89．47％,生化应答率为89．47％,病毒应答率为71．05％,对照组分别为83．34％、83．34％、66．67％（均P＞0．05）。随访6个月,联合治疗组的持续应答率为47．37％,而对照组为16．67％（P＜0．05）。两组副作用均有发热、乏力、胃肠道症状、白细胞下降、肌肉酸痛等（P＞0．05）。结论：CIFN联合病毒唑治疗慢性内型肝炎,可迅速缓解患者的症状体症,促进HCV－RNA阴转,停药6个月后的持续完全应答显著优于单干扰素。临床应用安全。