Sofosbuvir-based regimens for HCV in stage 4–stage 5 chronic kidney disease. A systematic review with meta-analysis

BackgroundHepatitis C is an important agent of liver damage in patients with chronic kidney disease and the advent of DAAs has dramatically changed the management of HCV positive patients, including those with advanced CKD. Sofosbuvir is the backbone of many anti-HCV regimens based on DAAs but it remains unclear whether it is appropriate for HCV-infected patients with stage 4–5 CKD.Study aims and designWe performed a systematic review of the literature with a meta-analysis of clinical studies in order to evaluate the efficacy and safety of SOF-based DAA regimens in patients with stage 4–5 CKD. The primary outcome was sustained viral response (as a measure of efficacy); the secondary outcomes were the frequency of SAEs and drop-outs due to AEs (as measures of tolerability). The random-effects model of DerSimonian and Laird was adopted, with heterogeneity and stratified analyses.ResultsThirty clinical studies (n = 1537 unique patients) were retrieved. The pooled SVR12 and SAEs rate was 0.99 (95% confidence intervals, 0.97; 1.0, I² = 99.8%) and 0.09 (95% CI, 0.05; 0.13, I² = 84.3%), respectively. The pooled SVR12 rate in studies with high HCV RNA levels at baseline was lower, 0.87 (95% CI, 0.75; 1.0, I² = 73.3%) (P < 0.001). The pooled drop-out rate due to AEs was 0.02 (95% CI, −0.01; 0.04, I² = 16.1%). Common serious adverse events were anemia (n = 26, 38%) and reduced eGFR (n = 14, 19%). SAEs were more common in studies adopting full-dose sofosbuvir (pooled rate of SAEs 0.15, 95% CI, 0.06; 0.25; I² = 80.1%) and in those based on ribavirin (0.15, 95% CI, 0.07; 0.23, I² = 95.8%). Six studies (n = 69 patients) reported eGFR levels at baseline/post- antiviral therapy; no consistent changes were found.ConclusionsSOF-based regimens appear safe and effective in patients with stage 4–5 CKD. Serum creatinine should be carefully monitored during therapy with SOF in patients with CKD. Randomized controlled studies in order to expand our knowledge on this point are under way.     

Sustained virologic response to direct-acting antiviral agents predicts better outcomes in hepatitis C virus-infected patients: A retrospective study

BACKGROUND Direct-acting antiviral agents(DAAs) are extremely effective in eradicating hepatitis C virus(HCV) in chronically infected patients. However, the protective role of the sustained virologic response(SVR) achieved by second-and thirdgeneration DAAs against the onset of hepatocellular carcinoma(HCC) and mortality is less well established.AIM To examine the occurrence of HCC or death from any cause in a retrospectiveprospective study of patients treated with DAAs.METHODS Patients were enrolled from a tertiary academic hospital center for liver disease management that collects subject data mainly from northeastern Italy. The study was conducted in 380 patients(age: 60 ± 13 years, 224 males, 32% with cirrhosis)treated with DAAs with or without SVR(95/5%), with a median follow up of 58 wk(interquartile range: 38-117). The baseline anthropometric features, HCV viral load, severity of liver disease, presence of extra-hepatic complications, coinfection with HIV and/or HBV, alcohol consumption, previous interferon use, alphafetoprotein levels, and renal function were considered to be confounders.RESULTS The incidence rate of HCC in patients with and without SVR was 1.3 and 59 per100 person-years, respectively(incidence rate ratio: 44, 95%CI: 15-136, P 0.001).Considering the combined endpoint of HCC or death from any cause, the hazard ratio(HR) for the SVR patients was 0.070(95%CI: 0.025-0.194, P 0.001). Other independent predictors of HCC or death were low HCV viremia(HR: 0.808, P =0.030), low platelet count(HR: 0.910, P = 0.041), and presence of mixed cryoglobulinemia(HR: 3.460, P = 0.044). Considering SVR in a multi-state model,the independent predictors of SVR achievement were absence of cirrhosis(HR:0.521, P 0.001) and high platelet count(HR: 1.019, P = 0.026). Mixed cryoglobulinemia predicted the combined endpoint in patients with and without SVR(HR: 5.982, P = 0.028 and HR: 5.633, P = 0.047, respectively).CONCLUSION DAA treatment is effective in inducing SVR and protecting against HCC or death.A residual risk of HCC persists in patients with advanced liver disease or with complications, such as mixed cryoglobulinemia or renal failure.     

Viral eradication restores normal iron status in chronic hepatitis C patients with abnormal iron studies

Introduction and objectivesAbnormal serum iron studies are seen in a third or more of patients with chronic hepatitis C infection (HCV), where they have been linked to accelerated fibrosis progression and increased risk of hepatocellular carcinoma and sometimes lead to concern for coexisting hereditary hemochromatosis. The aim of this study was to assess the effect of HCV eradication in patients with abnormal serum iron studies prior to treatment with direct-acting antiviral agents (DAAs).PatientsHCV-infected subjects with iron studies obtained before and after successful treatment with DAAs were identified (n = 27). All had one or more abnormal iron test before treatment.ResultsFollowing HCV eradication, serum iron, transferrin-iron saturation and ferritin levels decreased significantly (pre- versus post-treatment, p < 0.01 for each). Serum iron and/or transferrin-iron saturations normalized in 16/19 subjects and raised ferritin levels returned to the normal range in 14/18 subjects, including several with pretreatment transferrin-iron saturation >90% and/or serum ferritin >1000 ng/mL. Elimination of HCV infection was associated with a significant reduction in post-treatment ferritin levels even among subjects whose ferritin levels were within normal limits at baseline. Risk factors for other conditions associated with abnormal iron status were present in the few cases in which iron studies failed to normalize following DAA treatment.ConclusionsEradication of HCV infection restores normal iron status in most patients with abnormal iron tests, including those whose baseline parameters are suggestive of hemochromatosis.     

丙型肝炎抗病毒治疗研究进展

丙型肝炎由于进展隐匿、慢性率高及预后不良而倍受关注。研究发现，约20％慢性丙型肝炎患者将进展为肝硬化，约2．5％最终罹患肝癌。据估计，全球有1．7亿丙型肝炎病毒（HCV）携带者，我国人群HCV感染率约在3％左右。以干扰素为基础的治疗在临床上一直居于主导地位，特别是聚乙二醇化干扰素（Peg—IFN）联合利巴韦林的应用使病毒学应答率明显提高。但是，疗程长、有效率低、不良反应大等问题仍未得到根本解决。     

Elimination of hepatitis C virus infection from a hemodialysis unit and impact of treatment on the control of anemia

Introduction

In the interferon era, the treatment of hepatitis C virus (HCV) infection in patients on haemodialysis (HD) was limited due to the significant number of treatment-related adverse events (AEs). Direct-acting antivirals (DAAs) have demonstrated their efficacy and safety in the treatment of HCV in patients with advanced chronic kidney disease on haemodialysis. The objective of the study was to evaluate the success in eliminating HCV infection from our dialysis unit using DAAs, and to assess the impact of HCV elimination on clinical and analytical outcomes.

Use of direct-acting antiviral agents in hepatitis C virus-infected liver transplant candidates

Since the advent of direct acting antiviral(DAA) agents, chronic hepatitis C virus(HCV) treatment has evolved at a rapid pace. In contrast to prior regimen involving ribavirin and pegylated interferon, these newer agents are highly effective, well-tolerated, have shorter course of therapy and safer essentially in all HCV patients including those with advanced liver disease and following liver transplantation. Clinicians caring for HCV-infected patients on the liver transplant(LT) waitlist are often faced with a dilemma whether to treat HCV infection before or after liver transplantation. Sustained virological response(SVR) rates following HCV treatment may improve hepatic function sufficiently enough to negate the need for LT in certain patients. On the other hand, the decrease in MELD without improvement in quality of life in certain patients may lead to delay or dropout from potentially curative LT surgery list. In this context, our review focuses on the approach to and optimal timing of DAA-based treatment of HCV infection in LT candidates in the peri-transplant period.     

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。     

Consensus on management of hepatitis C virus infection in resource-limited Ukraine and Commonwealth of Independent States regions

Globally, 69.6 million individuals were infected with hepatitis C virus (HCV) infection in 2016. Of the six major HCV genotypes (GT), the most predominant one is GT1, worldwide. The prevalence of HCV in Central Asia, which includes most of the Commonwealth of Independent States (CIS), has been estimated to be 5.8% of the total global burden. The predominant genotype in the CIS and Ukraine regions has been reported to be GT1, followed by GT3. Inadequate HCV epidemiological data, multiple socio-economic barriers, and the lack of regionspecific guidelines have impeded the optimal management of HCV infection in this region. In this regard, a panel of regional experts in the field of hepatology convened to discuss and provide recommendations on the diagnosis, treatment, and pre-, on-, and posttreatment assessment of chronic HCV infection and to ensure the optimal use of cost-effective antiviral regimens in the region. A comprehensive evaluation of the literature along with expert recommendations for the management of GT1-GT6 HCV infection with the antiviral agents available in the region has been provided in this review. This consensus document will help guide clinical decision-making during the management of HCV infection, further optimizing treatment outcomes in these regions.     

Burden and challenges of heart failure in patients with chronic kidney disease. A call to action

Patients with the dual burden of chronic kidney disease (CKD) and chronic congestive heart failure (HF) experience unacceptably high rates of symptom load, hospitalization, and mortality. Currently, concerted efforts to identify, prevent and treat HF in CKD patients are lacking at the institutional level, with emphasis still being placed on individual specialty views on this topic. The authors of this review paper endorse the need for a dedicated cardiorenal interdisciplinary team that includes nephrologists and renal nurses and jointly manages appropriate clinical interventions across the inpatient and outpatient settings. There is a critical need for guidelines and best clinical practice models from major cardiology and nephrology professional societies, as well as for research funding in both specialties to focus on the needs of future therapies for HF in CKD patients. The implementation of cross-specialty educational programs across all levels in cardiology and nephrology will help train future specialists and nurses who have the ability to diagnose, treat, and prevent HF in CKD patients in a precise, clinically effective, and cost-favorable manner.     

Replication of clinical hepatitis B virus isolate and its application for selecting antiviral agents for chronic hepatitis B patients

AIM： To establish a cell model harboring replicative clinical hepatitis B virus （HBV） isolates and evaluate its application in individualized selection of anti-HBV agents for chronic hepatitis B （CHB） patients.
METHODS： The full-length HBV genomic DNA from 8 CHB patients was amplified by polymerase chain reaction （PCR）. All the patients were treated with lamivudine for at least seven months and finally became resistant to lamivudine. The amplified HBV DNA fragments were inserted into pHY106 vectors by Sap Ⅰ digestion. The recombinant plasmids containing 1.1 copies of HBV genome were transiently transfected into Huh7 cell line, and the levels of HBsAg, HBeAg and intercellular HBV replicative intermediates were determined by ELISA and Southern blot analysis, respectively, with or without lamivudine and adefovir treatment. The antiviral treatment with adefovir was administered to the patients and analyzed in parallel.
RESULTS： A total of 25 independent HBV isolates were obtained from the sera of 8 patients, each patient had at least two isolates. One isolate from each individual was selected and subcloned into pHY106 vector, including 5 isolates with YVDD mutation and 3 isolates with YIDD mutation. All recombinant plasmids harboring HBV isolates were transfected into Huh7 cells. The results indicated that HBV genome carried in HBV replicons of clinical HBV isolates could effectively replicate and express in Huh7 cells. Adefovir, but not lamivudine, inhibited HBV replication both in vitro and in vivo, and in vitro inhibition was dose-dependent.
CONCLUSION： The novel method described herein enables individualized selection of anti-HBV agents in clinic and is useful in future studies of antiviral therapy for CHB.     

NS3 protease inhibitors for treatment of chronic hepatitis C: Efficacy and safety

A new treatment paradigm for hepatitis C is that the treatment must include an existing direct-acting antiviral agent, namely, a protease inhibitor(PI) combined with PEGylated interferon-a and ribavirin. The currently mar-keted PIs and PIs in clinical trials have different mecha-nisms of action. The development of new PIs aims for an improved safety profile and higher effectiveness. This article reviews NS3/4A protease inhibitors, focusing on major criteria such as their effectiveness and safety. Specific attention is paid to dosing regimens and adverse event profiles of PIs administered in clinical settings.     

丙型肝炎肝硬化脾切除贲门周围血管离断术后的抗病毒疗效观察

我们对24例慢性丙型肝炎肝硬化合并脾功能亢进的患者进行了治疗,通过脾切除贲门周围血管离断术纠正外周血白细胞和血小板减少,术后2～4周开始聚乙二醇干扰素联合利巴韦林抗病毒治疗,疗程1年,随访24周,现报道如下.     

Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV infection and psychiatric disorders: An integrated analysis

Although direct‐acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection are highly efficacious and safe, treatment initiation is often limited in patients with neuropsychiatric disorders due to concerns over reduced treatment adherence and drug–drug interactions. Here, we report adherence, efficacy, safety and patient‐reported outcomes (PROs) from an integrated analysis of registrational studies using the pangenotypic DAA regimen of glecaprevir and pibrentasvir (G/P). Patients with chronic HCV genotypes 1‐6 infection with compensated liver disease (with or without cirrhosis) receiving G/P for 8, 12 or 16 weeks were included in this analysis. Patients were classified as having a psychiatric disorder based on medical history and/or co‐medications. Primary analyses assessed treatment adherence, efficacy (sustained virologic response at post‐treatment week 12; SVR12), safety and PROs. Among 2522 patients receiving G/P, 789 (31%) had a psychiatric disorder with the most common diagnoses being depression (64%; 506/789) and anxiety disorders (27%; 216/789). Treatment adherence was comparably high (>95%) in patients with and without psychiatric disorders. SVR12 rates were 97.3% (768/789; 95% CI = 96.2‐98.5) and 97.5% (1689/1733; 95% CI = 96.7‐98.2) in patients with and without psychiatric disorders, respectively. Among patients with psychiatric disorders, SVR12 rates remained >96% by individual psychiatric diagnoses and co‐medication classes. Overall, most adverse events (AEs) were mild‐to‐moderate in severity with serious AEs and AEs leading to G/P discontinuation occurring at similarly low rates in both patient populations. In conclusion, G/P treatment was highly efficacious, well‐tolerated and demonstrated high adherence rates in patients with chronic HCV infection and psychiatric disorders.     

Boceprevir plus peginterferon/ribavirin for treatment of chronic hepatitis C in Russia

AIM: to evaluate addition of boceprevir to peginterferon/ribavirin(PR) in Russian patients with chronic hepatitis C virus(HCV).METHODS: treatment-naive(t N) and treatmentexperienced(t E) patients(who had failed prior treatment with PR for ≥ 12 wk) with chronic HCV genotype 1 infection were enrolled in this placebocontrolled, double-blind study. All patients initially received PR for 4 wk. Patients randomized to control treatment then received PR for an additional 44 wk. t N patients randomized to triple therapy received boceprevir(800 mg three times daily) plus PR for 24 wk and then further therapy according to treatment week 8(t W8) HCV RNA levels. t E patients received boceprevir plus PR for 32 wk and then further therapy according to t W8 HCV RNA levels. treatment was discontinued for t N patients with detectable HCV RNA at t W24 and t E patients with detectable HCV RNA at t W12 because of futility. the primary efficacy end point was sustained virologic response(SVR) defined as undetectable HCV RNA 24 wk after completing all study therapy.RESULTS: SVR was 74.8% in the boceprevir plus PR arm compared with 46.2% in the control arm, with a stratification-adjusted treatment difference of 29.2%(95%CI: 16.4-41.5; P 0.0001). Rates of SVR were higher in the boceprevir arm in both t N and t E patient groups(t N 78.4% vs 56.3%; t E 69.4% vs 30.0%). Within t E patients, the rates of SVR were higher with boceprevir plus PR compared with PR, regardless of treatment failure type(null responder, partial responder, and relapser). Most patients receiving boceprevir plus PR in both t N(86%) and t E(71%) populations were eligible for reduced treatment duration. Anemia was increased in patients receiving boceprevir plus PR vs PR alone(47.2% vs 24.4%); there was a corresponding increase in ribavirin dose reduction and erythropoietin use. Among patients receiving boceprevir plus PR, SVR rates were similar in patients with anemia( 10 g/d L) and those without anemia(71.2% vs 77.4%).CONCLUSION: Regulatory approval has been obtained for boceprevir plus PR in Russian patients with HCV genotype 1 infection based on the results of this study.     

Effect of the baseline Y93H resistance-associated substitution in HCV genotype 3 for direct-acting antiviral treatment: real-life experience from a multicenter study in Sweden and Norway

Abstract

Background: The NS5A resistance-associated substitution (RAS) Y93H is found quite frequently (5–10%) at baseline in direct-acting antiviral agents (DAA) treatment-naïve genotype (GT) 3a patients when studied by the population-sequencing method (cut-off 20%). This RAS may impair HCV DAA treatment response, since it possesses a high fold in vitro resistance to daclatasvir (DCV) and velpatasvir (VEL) in GT 3. We investigated the effect of baseline Y93H in patients with GT 3a infection on treatment outcome, with or without resistance-based DAA-treatment during 2014–2017.

Patients/Methods: Treatment in the intervention group (n?=?130) was tailored to baseline resistance-findings by population-sequencing method. Detection of baseline Y93H above 20% prompted a prolonged treatment duration of NS5A-inhibitor and sofosbuvir (SOF) and/or addition of ribavirin (RBV). Patients without baseline Y93H in the intervention group and all patients in the control group (n?=?78) received recommended standard DAA-treatment.

Results: A higher sustained virologic response rate (SVR) in the intervention group was shown compared to the control group at 95.4% (124/130) and 88.5% (69/78), respectively (p?=?.06). All five patients with baseline Y93H in the intervention group achieved SVR with personalised treatment based on results from resistance testing; either with the addition of RBV or prolonged treatment duration (24w). In the control group, 2/4 patients with Y93H at baseline treated with ledipasvir/SOF/RBV or DCV/SOF without RBV, failed treatment.

Conclusion: The results from this real-life study are in accordance with the findings of the randomised controlled trials in 2015 and the EASL-guidelines of 2016, thus, baseline Y93H impacts on DCV and VEL treatment outcome.