Alpha-fetoprotein screening in patients with hepatitis C-induced cirrhosis who achieved a sustained virologic response in the direct-acting antiviral agents era

To the Editor:Hepatocellular carcinoma (HCC) is the most common primary livertumorandthethirdcauseofcancer-relateddeathsworldwide. HCC is the consequence of malignant transformation of hepatocytes and mainly occurs in patients with cirrhosis. Hepatitis C virus (HCV) chronic infection is a leading cause of end-stage liver diseaseandHCCintheWesterncountries[1].Theapprovalof direct-acting antiviral agents (DAAs) for the treatment of HCV has revolutionized the management of the disease, as no absolute contraindication to treatment exists and sustained virological response

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.

Use of direct-acting antiviral agents in hepatitis C virusinfected 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.

Association between direct-acting antiviral agents in hepatitis C virus treatment and hepatocellular carcinoma occurrence and recurrence:The endless debate

Since direct-acting antiviral agents(DAAs)have been introduced into hepatitis C virus treatment,the sustained viral response(SVR)rate has significantly increased to more than 95%.Scientific evidence supports the idea that SVR after interferon therapy has beneficial effects related to cirrhosis progression,resulting in a reduction in the incidence of hepatocellular carcinoma(HCC).However,a significant debate exists related to DAA impact on HCC development.We reviewed the current literature highlighting the controversial data related to DAA association with de novo HCC occurrence or recurrence and possible pathophysiology of HCC related to DAAs.After a review of the published literature,we believe that the current evidence does not confirm or repudiate a higher rate of de novo HCC occurrence or recurrence related to DAA therapy.More trials are needed to determine if there is an association between HCC occurrence or recurrence and DAA or if it is related to preexisting liver cirrhosis.

Direct-acting antivirals failed to reduce the incidence of hepatocellular carcinoma occurrence in hepatitis C virus associated cirrhosis: A real-world study

BACKGROUND Direct-acting antivirals(DAAs)revolutionized the treatment of chronic hepatitis C virus(HCV)-associated disease achieving high rates of sustained virological response(SVR).However,whether DAAs can reduce the occurrence of hepatocellular carcinoma(HCC)in patients with HCV-associated cirrhosis who are at high risk have not been concluded.AIM To investigate the effect of DAAs on the occurrence of HCC in patients with HCVassociated cirrhosis after achieving SVR.METHODS Of 427 inpatients with HCV-associated cirrhosis were enrolled in Tianjin Second People's Hospital from January 2014 to April 2020.118 patients weren’t received antiviral treatment with any reasons named non-antiviral treatment group,and 236 patients obtained from the 309 DAAs treatment patients according to the propensity score matching named DAAs treatment group.Demographic information and laboratory data were collected from baseline and the following up.Kaplan-Meier curve and Log-Rank test were used to compare the incidence and cumulative incidence of HCC between the two groups.Cox proportional risk regression was used to re-evaluate the risk factors for HCC.RESULTS HCC incidence was 4.68/100PY(95%CI,3.09-6.81)in the DAAs treatment group,while it was 3.00/100PY(95%CI,1.50-5.37)in the non-antiviral treatment group,and the relative risk was 1.82(95%CI,0.93-3.53,P>0.05).The incidence of HCC at 12,24,36 and 48 months was 3.39%,6.36%,8.47%and 10.17%in the DAAs treatment group,and it was 0%,0%,3.39%and 9.32%in the non-antiviral treatment group,respectively.Age>58[hazard ratio(HR)=1.089;95%CI,1.033-1.147;P=0.002]and liver stiffness measurement>27.85 kPa(HR=1.043;95%CI,1.022-1.065;P=0.000)were risk factors for HCC in all patients(n=427),and DAAs treatment didn’t show protective efficacy.CONCLUSION DAAs treatment seems failed to reduce the incidence of HCC occurrence in HCV-associated cirrhosis in 48 months,and even increased the incidence of HCC in 36 months.

Review of Clinically Relevant Drug Interactions with Next Generation Hepatitis C Direct-acting Antiviral Agents

In this review,we examine the pharmacokinetics and clinically relevant drug interactions of the newer generation direct-acting antivirals(DAAs)for the treatment of chronic hepatitis C,specifically sofosbuvir/velpatasvir(Epclusa®),sofosbuvir/velpatasvir/voxilaprevir(Vosevi®),glecaprevir/pibrentasvir(Maviret®),and elbasvir/grazoprevir(Zepatier®).We searched MEDLINE(1948-January 2020),Embase(1964-January 2020),Google,and GoogleScholar using the terms pharmacokinetics,drug interaction,drug metabolism,sofosbuvir,velpatasvir,Epclusa,voxilaprevir,Vosevi,glecaprevir,pibrentasvir,Maviret,elbasvir,grazoprevir,and Zepatier,from inception to January 13,2020.The search was limited to randomized controlled trials,in vitro studies,prospective and retrospective human studies,drug monographs,abstracts,and conference proceedings.All relevant published literature on pharmacokinetic and pharmacodynamic interactions involving DAAs were reviewed and the data extracted.Numerous clinically relevant drug-drug interactions(DDIs)were identified with the newer generation DAAs and commonly prescribed drugs.NS3/4A protease inhibitors are more likely to be involved in DDIs,followed by NS5A inhibitors and NS5B polymerase inhibitor.The majority of clinically relevant DDIs are predictable,according to known pharmacokinetic,pharmacodynamics,and physicochemical properties of DAAs;however,in select cases,unpredictable DDIs do occur.As expected,many drug interactions exist between newer generation DAAs and commonly prescribed medications.While the majority of clinically relevant interactions are predictable,many require therapeutic dose adjustment or careful selection of non-interacting drugs.In select cases,severe and unpredictable drug interactions can occur.Clinicians should consult hepatitis C virus pharmacotherapy experts and tertiary drug interaction resources when initiating DAA therapy in patients taking other medications.

Direct-acting Antiviral Agents Resistance-associated Polymorphisms in Chinese Treatment-na（i）ve Patients Infected with Genotype 1b Hepatitis C Virus

Background：It has been reported that several baseline polymorphisms of direct-acting antivirals （DAAs） agents resistance-associated variants （RAVs） would affect the treatment outcomes of patients chronically infected with hepatitis C virus （CHC）.The aim of this study is to investigate the prevalence of DAAs RAVs in treatment-na（i）ve GT1b CHC patients.Methods：Direct sequencing and ultra-deep sequencing of the HCV NS3,NS5A,and NS5B gene were performed in baseline serum samples of treatment-ha（i）ve patients infected with genotype lb hepatitis C virus （HCVs）.Results：One hundred and sixty CHC patients were studied.Complete sequence information was obtained for 145 patients （NS3）,148 patients （NS5A）,and 137 patients （NS5B）.Treatment-failure associated variants of DAAs were detected：56.6％ （82/145） of the patients presented S122G for simeprevir （NS3 protease inhibitor）;10.1％ （14/148） of the patients presented Y93H for daclatasvir and ledipasvir （NS5A protein inhibitors）;94.2％ （129/137） of the patients presented C316N for sofosbuvir （NS5B polymerase inhibitor）.Nearly,all of the DAAs RAVs detected by ultra-deep sequencing could be detected by direct sequencing.Conclusions：The majority of genotype lb CHC patients in China present a virus population carrying HCV DAAs RAVs.Pretreatment sequencing of HCV genome might need to be performed when patients infected with GTlb HCV receiving DAAs-containing regimens in China.Population sequencing would be quite quantified for the work.

Timing of Hepatitis C Virus Treatment in Liver Transplant Candidates in the Era of Direct-acting Antiviral Agents

Chronic hepatitis C virus(HCV)infection remains the leading indication for liver transplantation(LT)in the United States.While most patients with chronic HCV infection remain asymptomatic,up to one-third develop progressive liver disease resulting in cirrhosis.LT is often the only curative treatment once significant hepatic decompensation develops.However,antiviral therapy for HCV infection has advanced markedly in the past 5 years with the discovery and approval of direct-acting antiviral agents.These new regimens are well tolerated,of short duration and highly effective,unlike the traditional treatment with pegylated-interferon and ribavirin.As achieving sustained virological response becomes increasingly attainable for a majority of HCV-infected patients,concerns have been raised regarding the optimal timing of treatment for HCV infection in the setting of end-stage liver disease and during the peri-transplant period.On one hand,HCV treatment may improve hepatic function and negate the need for LT in some,which is crucial given the scarcity of donor organs and mortality on the waiting list in certain regions.On the other hand,HCV treatment may result in lowering the priority for LT without improving quality of life,thereby delaying potentially curative LT surgery.This review evaluates the evidence supporting the use of direct-acting antiviral agents in the period before and following LT.

Decade of optimizing therapy with direct-acting antiviral drugs and the changing profile of patients with chronic hepatitis C

Chronic infection with the hepatitis C virus(HCV)remains a major health problem affecting approximately 58 million people worldwide.In the era of interferon(IFN)-based regimens,patients particularly infected with genotypes 1 and 4 achieved a low response rate.The implementation of direct-acting antivirals changed the landscape of HCV treatment.The increase in effectiveness provided us with the hope of eliminating HCV as a significant public threat by 2030.In the following years,there was an observed improvement in the treatment of HCV with genotype-specific regimens and highly effective pangenotypic options that are the most recent stage of the revolution.The optimization of therapy was accompanied by changes in the patient profile from the beginning of the IFN-free era over time.Patients treated with antiviral therapies were younger in successive periods,less burdened with comorbidities and comedications,more frequently treatment-naïve and had less advanced liver disease.Before the IFN-free era,specific subpopulations such as patients with HCV/HIV coinfection,those with a history of previous treatment,patients with renal impairment or with cirrhosis had lower chances for a virologic response.Currently,these populations should no longer be considered difficult to treat.Despite the high effectiveness of HCV therapy,there is a small percentage of patients with treatment failure.However,they can be effectively retreated with pangenotypic rescue regimens.

Real-world effectiveness and safety of direct-acting antivirals in hepatitis C virus patients with mental disorders

BACKGROUND It is estimated that 58 million people worldwide are infected with the hepatitis C virus(HCV).Patients with severe psychiatric disorders could not be treated with previously available interferon-based therapies due to their unfavorable side effect profile.This has changed with the introduction of direct-acting antivirals(DAA),although their real-life tolerance and effectiveness in patients with different psychiatric disorders remain to be demonstrated.AIM To evaluate the effectiveness and safety of DAA in patients with various mental illnesses.METHODS This was a retrospective observational study encompassing 14272 patients treated with DAA for chronic hepatitis C in 22 Polish hepatology centers,including 942 individuals diagnosed with a mental disorder(anxiety disorder,bipolar affective disorder,depression,anxiety-depressive disorder,personality disorder,schizophrenia,sleep disorder,substance abuse disorder,and mental illness without a specific diagnosis).The safety and effectiveness of DAA in this group were compared to those in a group without psychiatric illness(n=13330).Antiviral therapy was considered successful if serum ribonucleic acid(RNA)of HCV was undetectable 12 wk after its completion[sustained virologic response(SVR)].Safety data,including the incidence of adverse events(AEs),serious AEs(SAEs),and deaths,and the frequency of treatment modification and discontinuation,were collected during therapy and up to 12 wk after treatment completion.The entire study population was included in the intent-to-treat(ITT)analysis.Per-protocol(PP)analysis concerned patients who underwent HCV RNA evaluation 12 wk after completing treatment.RESULTS Among patients with mental illness,there was a significantly higher percentage of men,treatmentnaive patients,obese,human immunodeficiency virus and hepatitis B virus-coinfected,patients with cirrhosis,and those infected with genotype 3(GT3)while infection with GT1b was more frequent in the population without psychiatric disorders.The cure rate calculated PP was not significantly different in the two groups analyzed,with a SVR of 96.9% and 97.7%,respectively.Although patients with bipolar disorder achieved a significantly lower SVR,the multivariate analysis excluded it as an independent predictor of treatment non-response.Male sex,GT3 infection,cirrhosis,and failure of previous therapy were identified as independent negative predictors.The percentage of patients who completed the planned therapy did not differ between groups with and without mental disorders.In six patients,symptoms of mental illness(depression,schizophrenia)worsened,of which two discontinued treatments for this reason.New episodes of sleep disorders occurred significantly more often in patients with mental disorders.Patients with mental illness were more frequently lost to follow-up(4.2%vs 2.5%).CONCLUSION DAA treatment is safe and effective in HCV-infected patients with mental disorders.No specific psychiatric diagnosis lowered the chance of successful antiviral treatment.

Histopathology and the predominantly progressive,indeterminate and predominately regressive score in hepatitis C virus patients after direct-acting antivirals therapy

BACKGROUND Histological changes after direct-acting antivirals(DAAs)therapy in hepatitis C virus(HCV)patients has not been elucidated.Whether the predominantly progressive,indeterminate and predominately regressive(P-I-R)score,evaluating fibrosis activity in hepatitis B virus patients has predictive value in HCV patients has not been investigated.AIM To identify histological changes after DAAs therapy and to evaluate the predictive value of the P-I-R score in HCV patients.METHODS Chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included.Sustained virologic response(SVR)was defined as an undetectable serum HCV RNA level at 24 wk after treatment cessation.The Ishak system and P-I-R score were assessed.Inflammation improvement and fibrosis regression were defined as a≥2-points decrease in the histology activity index(HAI)score and a≥1-point decrease in the Ishak fibrosis score,respectively.Fibrosis progression was defined as a≥1-point increase in the Ishak fibrosis score.Histologic improvement was defined as a≥2-points decrease in the HAI score without worsening of the Ishak fibrosis score after DAAs therapy.The P-I-R score was also assessed.“absolutely reversing or advancing”was defined as the same directionality implied by both change in the Ishak score and posttreatment P-I-R score;and“probably reversing or advancing”was defined as only one parameter showing directionality.RESULTS Thirty-eight chronic HCV patients with paired liver biopsy specimens before and after DAAs treatment were included.The mean age of these patients was 40.9±14.6 years and there were 53%(20/38)males.Thirty-four percent(13/38)of patients were cirrhotic.Eighty-two percent(31/38)of patients achieved inflammation improvement.The median HAI score decreased significantly after SVR(pretreatment 7.0 vs posttreatment 2.0,Z=-5.146,P=0.000).Thirty-seven percent(14/38)of patients achieved fibrosis improvement.The median Ishak score decreased significantly after SVR(pretreatment 4.0 vs posttreatment 3.0,Z=-2.354,P=0.019).Eighty-two percent(31/38)of patients showed histological improvement.The P-I-R score was evaluated in 61%(23/38)of patients.The progressive group showed lower platelet(P=0.024)and higher HAI scores(P=0.070)before treatment.In patients with stable Ishak stage after treatment:Progressive injury was seen in 22%(4/18)of patients,33%(6/18)were classified as indeterminate and regressive changes were seen in 44%(8/18)of patients who were judged as probably reversing by the Ishak and P-I-R systems.CONCLUSION Significant improvement of necroinflammation and partial remission of fibrosis in HCV patients occurred shortly after DAAs therapy.The P-I-R score has potential in predicting fibrosis in HCV patients.

Elastography as a predictor of liver cirrhosis complications after hepatitis C virus eradication in the era of direct-acting antivirals

Chronic inflammation due to hepatitis C virus(HCV)infection leads to liver fibrosis and rearrangement of liver tissue,which is responsible for the development of portal hypertension(PH)and hepatocellular carcinoma(HCC).The advent of direct-acting antiviral drugs has revolutionized the natural history of HCV infection,providing an overall eradication rate of over 90%.Despite a significant decrease after sustained virological response(SVR),the rate of HCC and liver-related complications is not completely eliminated in patients with advanced liver disease.Although the reasons are still unclear,cirrhosis itself has a residual risk for the development of HCC and other PH-related complications.Ultrasound elastography is a recently developed non-invasive technique for the assessment of liver fibrosis.Following the achievement of SVR,liver stiffness(LS)usually decreases,as a consequence of reduced inflammation and,possibly,fibrosis.Recent studies emphasized the application of LS assessment in the management of patients with SVR in order to define the risk for developing the complications of chronic liver disease(functional decompensation,gastrointestinal bleeding,HCC)and to optimize long-term prognostic outcomes in clinical practice.

Natural Products and Antiviral Resistance

Viral diseases are minacious with the potential for causing pandemics and treatment is complicated because of their inherent ability to mutate and become resistant to drugs. Antiviral drug resistance is a persistent problem that needs continuous attention by scientists, medical professionals, and government agencies. To solve the problem, an in-depth understanding of the intricate interplay between causes of antiviral drug resistance and potential new drugs specifically natural products is imperative in the interest and safety of public health. This review delves into natural product as reservoir for antiviral agents with the peculiar potentials for addressing the complexities associated with multi-drug resistant and emerging viral strains. An evaluation of the mechanisms underlying antiviral drug activity, antiviral drug resistance is addressed, with emphasis on production of broad-spectrum antiviral agents from natural sources. There is a need for continued natural product-based research, identification of new species and novel compounds.

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.

Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals

AIM To determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODS Transient elastography with controlled attenuation parameter(CAP) was used to assess hepatic steatosis post-sustained virological response(SVR);the CAP technology was not available in the United States at study initiation.Liver stiffness/fibrosis was measured before and 47 wk after treatment completion.Patients with genotype 3 and patients with cirrhosis were excluded.RESULTS One hundred and one patients were included in the study.Post-SVR there were decreases from baseline in alanine aminotransferase(ALT)(63.1 to 17.8 U/L),aspartate aminotransferase(51.8 to 21.5 U/L) and fibrosis score(7.4 to 6.1 k Pa)(P < 0.05).Post-SVR,48 patients(47.5%) had steatosis on CAP;of these,6.25% had advanced fibrosis.Patients with steatosis had higher body mass index(29.0 vs 26.1 kg/m2),glucose(107.8 vs 96.6 mg/d L),ALT(20.4 vs 15.3 mg/d L),CAP score(296.3 vs 212.4 d B/m) and fibrosis score(7.0 vs 5.3 k Pa);P < 0.05.Interestingly,compared to baseline,both patients with and without steatosis had change in fibrosis score post-SVR(7.7 k Pa vs 7.0 k Pa and 7.0 k Pa vs 5.3 k Pa);alternatively,(P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness(≥ 7 k Pa).CONCLUSION Fatty liver is very common in hepatitis C virus(HCV) patients post-SVR.These patients continue to have elevated mean fibrosis score(≥ 7 k Pa) compared to those without fatty liver;some have advanced fibrosis.Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.

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.

Peginterferon alfa-2a for the treatment of chronic hepatitis C in the era of direct-acting antivirals

BACKGROUND: The availability of novel direct-acting antivirals (DAAs) represents a new era of curative hepatitis C virus (HCV) treatment, with over 95% of patients infected with HCV genotype 1 achieving sustained virological response (SVR). Nevertheless, the majority of patients globally are unable to access these treatments because of cost and infrastructure constraints and, thus, remain untreated and uncured. DATA SOURCE: Relevant articles of peginterferon (PegIFN)-based treatments in HCV and sofosbuvir-based treatments, simeprevir, daclatasvir/asunaprevir, ritonavir-boosted paritaprevir/ombitasvir/dasabuvir, and grazoprevir/elbasvir, were searched in PubMed database, including general population and special population. RESULTS: PegIFN in combination with ribavirin remains an important and relevant option for some patients, achieving SVR rates of up to 79% in genotype 1 and 89% in genotype 2 or 3 infections, which increases for patients with favorable IL28B genotypes. Triple therapy of DAA plus PegIFN/ribavirin is effective in treating difficult-to-cure patients infected with HCV genotype 3 or with resistance-associated variants. Owing to its long history in HCV management, the efficacy, tolerability and long-term outcomes associated with PegIFN alfa-2a are well established and have been validated in large-scale studies and in clinical practice for many populations. Furthermore, emerging data show that IFN-induced SVR is associated with lower incidences of hepatocellular carcinoma compared with DAAs. On the contrary, novel DAAs have yet to be studied in special populations, and long-term outcomes, particularly tumor development and recurrence in patients with cirrhosis and/or hepatocellular carcinoma, and reactivation of HBV in dually infected patients, are still unclear. CONCLUSION: In this interferon-free era, PegIFN-based regimens remain a safe and effective option for selected HCV patients.