Are metabolic factors still important in the era of direct antiviral agents in patients with chronic hepatitis C?

The high rate of sustained viral response(SVR)to boceprevir or telaprevir-based triple therapy in hepatitis C(HCV)-related,non-cirrhotic na ve patients or relapsers to previous antiviral treatment leads clinicians to believe that the impact of metabolic host factors on SVR is minimal when triple therapy is used,unlike what is observed with the peginterferon and ribavirin schedules.This concept is strongly expressed by some opinion leaders on the basis of the data derived from subanalyses of registrative trials as well as from a post-hoc analysis of the phaseⅡC208 clinical trial.The perception of unrestrainable therapeutic success with the use of newer,more powerful antivirals is now reinforced by the brilliant results obtained with sofosbuvir,an HCV NS5B polymerase inhibitor,as well as by the data from the phaseⅡandⅢstudies on the various combinations of second-generation NS3/4A inhibitors and NS5A and/or NS5B inhibitors.However,a great deal of concern has emerged from the real world scenario in which patients are often older and have more comorbidities than patients in the"world of trials".Furthermore,many of them have advanced fibrosis and previous failure with peginterferon and ribavirin treatment.Some data from the recent literature suggest that the host metabolic factors may play a minor but non-negligible role in these difficult-to-treat patients,an issue that will hopefully be investigated in further studies.This editorial aims to provide a detailed analysis of the role that host metabolic factors played in the past and what role they may play in the era of direct antiviral agents.

Hepatitis C virus reinfection after liver transplantation: Is there a role for direct antiviral agents?

Recurrence of hepatitis C virus(HCV)infection following liver transplantation(LT)is almost universal and can accelerate graft cirrhosis in up to 30%of patients.The development of effective strategies to treat or prevent HCV recurrence after LT remains a major challenge,considering the shortage of donor organs and the accelerated progression of HCV in LT recipients.Standard antiviral therapy with pegylated-interferon plus ribavirin is the current treatment of choice for HCV LT recipients,even though the combination is not as effective as it is in immunocompetent patients.A sustained virological response in the setting of LT improves patient and graft survival,but this is only achieved in 30%-45%of patients and the treatment is poorly tolerated.To improve the efficacy of pre-and post-transplant antiviral therapy,a new class of potent direct-acting antiviral agents (DAAs)has been developed.The aim of this review is to summarize the use of DAAs in LT HCV patients.PubMed,Cochrane Library,MEDLINE,EMBASE,Web of Science and clinical trial databases were searched for this purpose.To date,only three clinical studies on the topic have been published and most of the available data are in abstract form.Although a moderately successful early virological response has been reported,DAA treatment regimens were associated with severe toxicity mitigating their potential usefulness.Moreover,the ongoing nature of data,the lack of randomized studies,the small number of enrolled patients and the heterogeneity of these studies make the results largely anecdotal and questionable.In conclusion,large welldesigned clinical studies on DAAs in HCV LT patients are required before these drugs can be recommended after transplantation.

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 per 100 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.

Outcomes assessment of hepatitis C virus-positive psoriatic patients treated using pegylated interferon in combination with ribavirin compared to new Direct-Acting Antiviral agents

AIM To evaluate the outcomes in biological treatment and quality of life of psoriatic patients with chronic hepatitis C(CHC) treated with new Direct-Acting Antiviral agents(DAAs) compared to pegylated interferon-2α plus ribavirin(P/R) therapy.METHODS This is a retrospective study involving psoriatic patients in biological therapy who underwent anti-hepatitis C virus(HCV) treatment at the Department of Dermatology Galeazzi Orthopaedic Institute Milan, Italy from January 2010 to November 2017. The patients were divided into two groups: patients that underwent therapy with DAAs and patients that underwent HCV treatment with P/R. Patients were assessed by a dermatologist for psoriasis symptoms, collecting Psoriasis Area Severity Index(PASI) scores and the Dermatology Quality of Life Index(DLQI). PASI and DLQI scores were evaluated 24 wk after the end of HCV treatment and were assumed as an outcome of the progression of psoriasis. Switching to a different b DMARD was considered as an inadequate response to biological therapy. The dropout of HCV therapy and sustained virological response(SVR) were considered as outcomes of HCV therapy.RESULTS Fifty-nine psoriatic patients in biological therapy underwent antiviral therapy for CHC. Of this, 27 patients were treated with DAAs and 32 with P/R. After 24 wk post treatment, the DLQI and the PASI scores were significantly lower(P < 0.001 and P < 0.005, respectively) in the DAAs group compared with P/R group. None of the patients in the DAAs group(0/27) compared to 8 patients of the P/R group(8/32) needed a shift in biological treatment.CONCLUSION DAAs seem to be more effective and safe than P/R in HCV-positive psoriatic patients on biological treatment. Fewer dermatological adverse events may be due to interferon-free therapy.

三种DAAs方案治疗慢性丙型肝炎患者两年随访研究

目的分析不同直接抗病毒药物(DAAs)治疗慢性丙型肝炎(CHC)患者的疗效,随访观察两年结果。方法2018年1月~2020年12月我院收治的CHC患者123例,其中接受索磷布韦/维帕他韦(SOF/VEL)治疗52例,接受艾尔巴韦/格拉瑞韦(EBR/GZR)治疗43例,接受来迪派韦/索磷布韦(LDV/SOF)治疗28例,均连续治疗12 w,随访24 m。采用实时荧光定量RT-PCR法检测血清HCV RNA,比较不同方案治疗患者快速病毒学应答(RVR)、早期病毒学应答(EVR)、治疗结束时病毒学应答(ETVR)和持续病毒学应答(SVR)情况。结果SOF/VEL、EBR/GZR和LDV/SOF治疗患者RVR分别为96.2%、93.0%和92.9%,EVR分别为98.1%、97.7%和96.4%,ETVR和SVR均为100.0%,组间疗效比较,差异均无统计学意义(均P>0.05);在治疗过程中,SOF/VEL、EBR/GZR和LDV/SOF治疗组出现恶心、乏力和头晕等不良反应发生率分别为13.5%、11.6%和21.4%,组间比较,差异无统计学意义(P>0.05);在三组获得SVR者,分别有45例、36例和23例完成2年监测随访,结果均未发生病毒学复发和病情反复情况,也未出现肝癌发生。结论由于我国CHC患者以GT1b基因型感染为主,应用SOF/VEL、EBR/GZR或LDV/SOF抗病毒治疗效果均好,较长期的观察病情无反复。

Hepatitis B reactivation in patients receiving direct-acting antiviral therapy or interferon-based therapy for hepatitis C:A systematic review and meta-analysis

AIM To assess the incidence of hepatitis B virus(HBV) reactivation in patients receiving direct-acting antiviral agent(DAA)-based therapy or interferon(IFN)-based therapy for hepatitis C and the effectiveness of preemptive antiHBV therapy for preventing HBV reactivation.METHODS The Pub Med, MEDLINE and EMBASE databases were searched, and 39 studies that reported HBV reactivation in HBV/hepatitis C virus coinfected patients receiving DAAbased therapy or IFN-based therapy were included. The primary outcome was the rate of HBV reactivation. The secondary outcomes included HBV reactivation-related hepatitis and the effectiveness of preemptive anti-HBV treatment with nucleos(t)ide analogues. The pooled effects were assessed using a random effects model. RESULTS The rate of HBV reactivation was 21.1% in hepatitis Bsurface antigen(HBs Ag)-positive patients receiving DAAbased therapy and 11.9% in those receiving IFN-based therapy. The incidence of hepatitis was lower in HBs Agpositive patients with undetectable HBV DNA compared to patients with detectable HBV DNA receiving DAA therapy(RR = 0.20, 95%CI: 0.06-0.64, P = 0.007). The pooled HBV reactivation rate in patients with previous HBV infection was 0.6% for those receiving DAA-based therapy and 0 for those receiving IFN-based therapy, and none of the patients experienced a hepatitis flare related to HBV reactivation. Preemptive anti-HBV treatment significantly reduced the potential risk of HBV reactivation in HBs Agpositive patients undergoing DAA-based therapy(RR = 0.31, 95%CI: 0.1-0.96, P = 0.042).CONCLUSION The rate of HBV reactivation and hepatitis flare occurrence is higher in HBs Ag-positive patients receiving DAA-based therapy than in those receiving IFN-based therapy, but these events occur less frequently in patients with previous HBV infection. Preemptive anti-HBV treatment is effective in preventing HBV reactivation.

Chronic hepatitis C,atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral treatments?

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro-atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease.

Real life efficacy and safety of direct-acting antiviral therapy for treatment of patients infected with hepatitis C virus genotypes 1, 2and 3 in northwest China

BACKGROUND Regimens involving direct-acting antiviral agents(DAAs)are recommended for the treatment of infection with hepatitis C virus(HCV)genotypes 1,2 and 3.But real-world data is still not enough,especially in Asia.AIM To investigate the efficacy and safety of DAA-based regimens in a real-life setting in China.METHODS This study included 366 patients infected with HCV genotypes 1,2 and 3,with or without cirrhosis,who were observed between May 2015 and December 2018.They were treated with ledipasvir and sofosbuvir(SOF)(genotype 1)with or without ribavirin(RBV),SOF and RBV(genotype 2),or SOF and daclatasvir(genotype 3),with or without RBV,for 12 or more wk.The participants’sustained virological responses(SVR)at post-treatment week 12(SVR12)was the primary endpoint.The occurrence of adverse events and drug-drug interactions were recorded.RESULTS In the 366 patients,genotype 1(59.0%)was the most common genotype,followed by genotypes 2(34.4%)and 3(6.6%).Liver cirrhosis was diagnosed in 154(42.1%)patients.Fifty(13.7%)patients were treatment-experienced.Intention-to-treat analysis revealed that SVR12 was 86.3%(316/366).For modified intention-totreat analysis,SVR12 was achieved in 96.6%of overall patients(316/327),96.3%in patients with genotype 1,97.5%in those with genotype 2,and 95.0%in those with genotype 3.Most of the treatment failures were due to lack of follow-up(3cases had non-responses,1 had virological breakthrough,11 relapsed and 36 did not participate in the follow-up).There was no significant difference in SVR between different genotypes and liver statuses(P<0.05).Patients with lower alanine aminotransferase levels at baseline who achieved an end of treatment response were more likely to achieve SVR12(P<0.05).High SVR was observed regardless of age,gender,liver status,alpha-fetoprotein,HCV RNA levels or history of antiviral therapy(P>0.05 for all).The cumulative hepatocellular carcinoma occurrence and recurrence rate after using the DAAs was 0.9%.Most of the adverse events were mild.We found two cases of special adverse events.One case involved facial and bilateral lower extremity edema,and the other case showed an interesting change in lipid levels while on medication.No severe adverse events were noted.CONCLUSION The DAA-based regimens tested in this study have excellent effectiveness and safety in all patients infected with HCV genotypes 1,2 and 3,including those with cirrhosis.

Hepatitis C virus cures after direct acting antiviral-related drug-induced liver injury: Case report

The United States Food and Drug Administration recently warned that the direct acting antiviral(DAA) combination hepatitis C virus(HCV) treatment of Paritaprevir, Ombitasvir, Dasabuvir, Ritonavir, and Ribavirin(PODr + R) can cause severe liver injury in patients with advanced liver disease. Drug induced liver injury was observed in a small number of patients with decompensated cirrhosis treated with other DAAs, but has not been reported in patients with compensated cirrhosis. We report a case of a 74-year-old woman with chronic HCV and Child-Pugh class A cirrhosis(compensated cirrhosis) treated with PODr + R. The patient presented on day 14 of PODr + R therapy with jaundice and new-onset ascites. Her total bilirubin level increased to 23 mg/dL and international normalized ratio rose to 1.65, while aminotransferase levels remained relatively stable. Hepatitis C treatment was discontinued on day 24 and she gradually recovered. Follow-up testing showed that she achieved a sustained virologic response. In conclusion, hepatic decompensation developed within two weeks of starting treatment withPODr + R in a patient with Child-Pugh class A cirrhosis and was characterized by jaundice and ascites with stable aminotransferase levels. Careful monitoring is warranted in patients with HCV-related cirrhosis treated with PODr + R.

Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: A few lights and many shadows

With the introduction of direct-acting antiviral agents(DAA), the rate of sustained virological response(SVR) in the treatment of hepatitis C virus(HCV) has radically improved to over 95%. Robust scientific evidence supports a beneficial role of SVR after interferon therapy in the progression of cirrhosis, resulting in a decreased incidence of hepatocellular carcinoma(HCC). However, a debate on the impact of DAAs on the development of HCC is ongoing. This review aimed to analyse the scientific literature regarding the risk of HCC in terms of its recurrence and occurrence after the use of DAAs to eradicate HCV infection. Among 11 studies examining HCC occurrence, the de novo incidence rate ranged from 0 to 7.4%(maximum follow-up: 18 mo). Among 18 studies regarding HCC recurrence, the rate ranged from 0 to 54.4%(maximum "not well-defined" followup: 32 mo). This review highlights the major difficulties in interpreting data and reconciling the results of the included studies. These difficulties include heterogeneous cohorts, potential misclassifications of HCC prior to DAA therapy, the absence of an adequate control group, short follow-up times and different kinds of follow-up. Moreover, no clinical feature-based scoring system accounts for the molecular characteristics and pathobiology of the tumours. Nonetheless, this review does not suggest that there is a higher rate of de novo HCC occurrence or recurrence after DAA therapy in patients with previous HCV infection.

Hepatitis C and renal transplantation in era of new antiviral agents

Data from World Health Organization estimates that the hepatitis C virus(HCV) prevalence is 3% and approxi-mately 71 million persons are infected worldwide. HCV infection is particularly frequent among patients affected by renal diseases and among those in dialysis treatment. In addition to produce a higher rate of any cause of death, HCV in renal patients and in renal transplanted patients produce a deterioration of liver disease and is a recognized cause of transplant glomerulopathy, new onset diabetes mellitus and lymphoproliferative disorders. Treatment of HCV infection with interferon alpha and/or ribavirin had a poor efficacy. The treatment was toxic, expensive and with limited efficacy. In the post-transplant period was also cause of severe humoral rejection. In this review we have highlighted the new direct antiviral agents that have revolutionized the treatment of HCV both in the general population and in the renal patients. Patients on dialysis or with low glomerular filtration rate were particularly resistant to the old therapies, while the direct antiviral agents allowed achieving a sustained viral response in 90%- 100% of patients with a short period of treatment. This fact to date allows HCV patients to enter the waiting list for transplantation easier than before. These new agents may be also used in renal transplant patients HCV -positive without relevant clinical risks and achieving a sustained viral response in almost all patients. New drug appears in the pipeline with increased profile of efficacy and safety. These drugs are now the object of several phases Ⅱ, Ⅲ clinical trials.

Retreatment of patients with treatment failure of directacting antivirals: Focus on hepatitis C virus genotype 1b

The recent development of direct-acting antiviral agents(DAAs) against hepatitis C virus(HCV) infection could lead to higher sustained virological response(SVR) rates, with shorter treatment durations and fewer adverse events compared with regimens that include interferon. However, a relatively small proportion of patients cannot achieve SVR in the first treatment, including DAAs with or without peginterferon and/or ribavirin. Although retreatment with a combination of DAAs should be conducted for these patients, it is more difficult to achieve SVR when retreating these patients because of resistance-associated substitutions(RASs) or treatment-emergent substitutions. In Japan, HCV genotype 1 b(GT1 b) is founded in 70% of HCVinfected individuals. In this minireview, we summarize the retreatment regimens and their SVR rates for HCV GT1 b. It is important to avoid drugs that target the regions targeted by initial drugs, but next-generation combinations of DAAs, such as sofosbuvir/velpatasvir/voxilaprevir for 12 wk or glecaprevir/pibrentasvir for 12 wk, are proposed to be potential solution for the HCV GT1 b-infected patients with treatment failure, mainly on a basis of targeting distinctive regions. Clinicians should follow the new information and resources for DAAs and select the proper combination of DAAs for the retreatment of HCV GT1 b-infected patients with treatment failure.

直接抗病毒药物治疗对丙型肝炎患者肝外疾病预后的影响

HCV感染者的预后不仅取决于肝脏病变,还取决于肝外后遗症。直接抗病毒药物(DAAs)作为当前治疗丙型肝炎的一线用药,使越来越多的患者获得持续病毒学应答及临床治愈,但其对肝外疾病转归的影响尚不清楚。本文就DAAs治疗对丙型肝炎患者肝外疾病预后的影响作一综述,提示丙型肝炎治愈患者仍需进行长期随访监测。

直接抗病毒药物治疗丙型肝炎肝硬化的疗效及影响因素分析

目的探讨丙型肝炎肝硬化患者经直接抗病毒药物(direct-acting antiviral agents,DAAs)治疗后的疗效和相关影响因素。方法回顾性分析2017年9月至2022年4月就诊于四川省人民医院感染科的初治丙型肝炎肝硬化患者,分别经索磷布韦/维帕他韦±利巴韦林、来迪派韦/维帕他韦±利巴韦林、艾尔巴韦/格拉瑞韦等直接抗病毒药物治疗后的病毒学应答、血清生化学和肝脏纤维化程度的改善情况,并探讨其影响因素。结果纳入的54例丙型肝炎肝硬化患者中,代偿期肝硬化患者37例,失代偿期肝硬化患者17例。年龄(57.65±9.58)岁,其中24例(44.44%)为男性,患者基线平均HCV RNA载量为(5.60±0.90)lgIU/mL。经治疗后,90.74%的患者获得快速病毒学应答(rapid virologic response,RVR),治疗结束时病毒学应答率(end-of-treatment virologic response rate,ETVR)达100%。1例基因3b型患者在治疗结束后12周出现病毒复发,总人群中有98.15%的患者在治疗结束后12周获得持续病毒学应答(sustained virologic response 12 weeks,SVR12),其中失代偿期肝硬化患者100%获得SVR12。肝硬化总人群的血清ALT、AST、ALB、TBIL及FIB-4、APRI评分显著改善,PLT、Scr无明显变化。进一步亚组分析结果显示,年龄<60岁患者的ALB水平在治疗4周迅速出现显著改善,且持续至治疗结束12周,而年龄≥60岁患者ALB的显著改善延迟至治疗结束12周;HCV RNA<1×10^(6)IU/mL组患者的ALB在治疗4周及治疗结束12周持续出现显著改善,而HCV RNA≥1×10^(6)IU/mL组患者的ALB水平仅在治疗结束12周出现显著改善;基因1b型组治疗4周的FIB-4、APRI评分显著改善,治疗结束时及结束12周均出现ALB的显著改善,而基因非1b型组的FIB-4评分无显著改善,治疗结束12周才出现ALB的显著改善;代偿期肝硬化及失代偿期肝硬化患者在治疗初期至治疗结束12周的观察周期内,均出现血生化及无创肝纤维化指标的显著改善,两组的变化趋势基本一致,SVR12率差异无统计学意义(P>0.05)。结论经DAAs治疗后,丙肝肝硬化患者可获得较高的SVR12率,血清生化学及肝脏纤维化程度显著改善。高病毒载量、高龄、基因非1b型是短期内(治疗结束12周)影响血清生化学及肝脏纤维化指标改善的可能因素。

索非布韦/达克拉韦治疗CHC患者血清血管性血友病因子和可溶性血管黏附因子1水平变化

目的本研究旨在探讨直接抗病毒药物治疗的慢性丙型肝炎(CHC)患者的疗效及其对血清细胞因子水平的影响。方法2020年6月~2022年12月我院诊治的38例CHC患者和38例丙型肝炎肝硬化患者,均接受索非布韦(SOF)、盐酸达克拉韦(DCV)和利巴韦林三联疗法治疗12周。采用RT-PCR法检测血清HCV RNA载量,采用ELISA法检测血清血管性血友病因子(vWF)、可溶性血管黏附因子1(sVCAM-1)和白细胞介素-6(IL-6)水平。结果本组丙型肝炎肝硬化患者快速病毒学应答、治疗结束病毒学应答和持续病毒学应答率分别为81.5%、89.5%和97.4%,与CHC组的89.5%、92.1%和100.0%比,无显著性差异(P>0.05);在治疗结束时,肝硬化组外周血白细胞和血小板计数分别为(4.7±0.9)×10^(9)/L和(139.5±42.1)×10^(9)/L,显著低于CHC组【分别为(6.8±2.2)×10^(9)/L和(275.6±65.3)×10^(9)/L,P<0.05】,而基于4因子的肝纤维化指数(FIB4)和天冬氨酸氨基转移酶/血小板计数指数(APRI)评分分别为(2.8±1.6)和(0.6±0.3),显著高于CHC组【分别为(0.7±0.9)和(0.2±0.1),P<0.05】;肝硬化组血清vWF和sVCAM-1水平分别(134.3±44.3)ng/mL和(36.6±14.9)ng/mL,显著高于CHC组【分别为(103.9±33.0)ng/mL和(18.7±8.9)ng/mL,P<0.05】。结论应用DAAs治疗HCV感染患者可获得良好的抗病毒疗效,且能有效改善血管内皮功能,其临床意义还有待进一步探讨。

不同抗病毒治疗方案对慢性丙型肝炎持续应答患者肝细胞癌发生的影响

目的研究直接抗病毒药物(DAAs)与利巴韦林(PR)方案治疗慢性丙型肝炎患者获得持续病毒学应答后肝细胞癌发生率的差异,并分析其危险因素。方法回顾性分析河北医科大学第三医院2006年1月以来符合纳入标准的慢性丙型肝炎住院患者的临床病例资料,根据患者治疗方案将其分为DAAs组和PR组。使用倾向性匹配分析均衡两组间基线资料。采用Kaplan-Meier法估计发生率,并用Log-rank法比较两组间差异,单因素和多因素Cox比例风险模型分析肝细胞癌发生的危险因素。结果在369名符合纳入条件的患者中,229(62.1%)例应用PR方案治疗,140(37.9%)例应用DAAs治疗,经倾向性匹配后每组各106例。两组肝细胞癌的4年发生率分别为:7.9%和10.2%,无统计学意义(P=0.070)。多因素分析显示:丙肝初治时的年龄(HR=1.093,95%CI:1.007,1.186)、合并糖尿病(HR=9.988,95%CI:2.093,47.662)、肝硬化(HR=9.422,95%CI:1.079,82.250)、基线AFP水平≥10 ng/mL(HR=5.683,95%CI:1.100,29.369)以及HCV RNA高水平复制(HR=2.877,95%CI:1.203,6.878)为获得持续病毒学应答后慢性丙型肝炎患者发生肝细胞癌的独立危险因素。结论经不同抗病毒治疗方案获得持续病毒性应答的丙肝患者,肝细胞癌4年发生率无差异。

泛基因型与特异基因型DAAs方案精准治疗基因1b型慢性丙型肝炎患者疗效对比分析

目的比较采用泛基因型与特异基因型直接抗病毒药物(DAAs)方案精准治疗基因1b型慢性丙型肝炎(CHC)患者的疗效。方法2018年1月~2020年6月我院诊治的基因1b型CHC患者75例,其中34例对照组患者接受泛基因型DAAs治疗,即19例接受索非布韦/维帕他韦口袋,15例口服索磷布韦/达拉他韦;41例研究组接受特异基因型DAAs治疗,即23例口服艾尔巴韦/格拉瑞韦,18例口服奥比帕利/达塞布韦。两组均持续治疗12周。采用实时荧光定量PCR法检测血清HCV RNA。比较两组超快速病毒学应答(SRVR)、快速病毒学应答(RVR)、早期病毒学应答(EVR)和持续病毒学应答(SVR)。结果在治疗12周末,研究组血清ALT和AST水平分别为(31.9±4.1)U/L和(32.5±4.1)U/L,与对照组[分别为(32.7±4.2)U/L和(31.9±3.7)U/L,P>0.05]比,无显著性差异;研究组SRVR、RVR、EVR和SVR分别为87.8%、97.6%、100.0%和100.0%,与对照组(分别为88.2%、94.1%、100.0%和100.0%)比,差异均无统计学意义(P>0.05);索非布韦/维帕他韦治疗患者SRVR、RVR、EVR和SVR分别为84.2%、100.0%、100.0%和100.0%,索磷布韦/达拉他韦治疗患者分别为86.7%、93.3%、100.0%和100.0%,艾尔巴韦/格拉瑞韦治疗患者分别为91.3%、100.0%、100.0%和100.0%,奥比帕利/达塞布韦治疗患者分别为88.9%、94.4%、100.0%和100.0%,四组所有病毒学应答率均无显著性差异(P>0.05);治疗期间两组不良反应发生率为11.8%对12.2%,差异无统计学意义(P>0.05)。结论当前应用的无论是泛基因型还是特异基因型DAAs方案治疗基因1b型CHC患者均具有良好的疗效,且安全性良好。是否可以不区分感染病毒基因型选择药物治疗,值得进一步研究。

我国丙型肝炎肝硬化患者DAA治疗现状及短期预后的研究

目的了解丙型肝炎肝硬化患者直接抗病毒药物(DAA)治疗现状、短期预后和影响因素。方法选取2015年1月至2019年11月期间于瑞金医院感染科诊治的丙型肝炎肝硬化患者,收集其数据,研究基线特征、DAA方案及疗效和预后的关系。结果共入组161例,DAA治疗者149例;代偿组122例,失代偿组27例;两组在年龄、性别、HCV基因型及干扰素治疗史等方面无显著性差别;两组疗效与安全性均良好,其中SVR12率(99.17%比96.25%,P=0.325)和SVR24率(96.64%比92.0%,P=0.614)均无明显差异;基线肝硬化失代偿期患者中发生肝病进展的比例明显高于代偿期患者(50%vs.13.75%,P=0.000);基线肝硬化失代偿是DAA治疗后短期预后的独立危险因素(HR 6.765,95%Cl:2.866~15.969,P=0.000)。结论基线肝硬化失代偿是DAA治疗后短期预后的独立预测因素。

基因1b型慢性丙型肝炎患者DAAs天然耐药突变分析

目的探讨未经抗病毒治疗的基因1b型慢性丙型肝炎患者天然耐药突变情况。方法应用RT-PCR法扩增丙型肝炎病毒（HCV）NS3及NS5B部分片段序列，用克隆测序方法进行核苷酸序列测定。在氨基酸水平与已有报道的蛋白酶抑制剂耐药突变位点（V36、T54、V55、Q80、R155、A156、D168和V170）和聚合酶抑制剂耐药突变位点（$282、C316、S365、M414、L419、M423和Y448）进行比较。结果9例患者中3例存在直接抗病毒药物（DAAs）耐药突变，在3例检测到蛋白酶抑制剂耐药突变的患者中2例为T54S突变，1例为A156T突变，存在A156T突变的患者中同时检测到聚合酶抑制剂耐药突变M414L。结论中国DAAs初治患者中天然存在着蛋白酶抑制剂耐药突变T54S、A156T和聚合酶抑制剂耐药突蛮M414L。

丙型病毒性肝炎供者器官在实体器官移植中的应用现状与展望

丙型病毒性肝炎供者器官作为一种边缘性器官已经被应用于实体器官移植中,在有效缓解器官短缺现况的同时,也面临着一些挑战,如丙型肝炎病毒(HCV)传播。但随着直接抗病毒药物的出现和应用,丙型病毒性肝炎的治愈逐渐成为现实,这也为丙型病毒性肝炎患者成为器官移植供者奠定了基础。目前,在抗病毒药物的辅助治疗下,丙型病毒性肝炎供者实体器官移植取得了一定的疗效。因此,本文总结丙型病毒性肝炎供者肾脏、心脏、肺脏及肝脏等移植的研究现状,就丙型病毒性肝炎供者在实体器官移植中的应用情况及抗病毒药物辅助治疗的安全有效性做一综述,探究丙型病毒性肝炎供者在实体器官移植中可行性,以期为扩大器官移植供体池提供参考,减少终末期疾病患者器官移植的等待时间。