Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis

Publications>Journals>Journal of Clinical and Translational Hepatology>Article Full Text ORIGINAL ARTICLE OPEN ACCESS Efficacy and Safety of All-oral Emitasvir and Sofosbuvir in Patients with Genotype 1b HCV Infections without Cirrhosis Huiying Rao1,Xingxiang Yang2,Youwen Tan3,Qin Ning4,Daokun Yang5,Jiefei Wang6,Yongfeng Yang7,Sujun Zheng8,Dongliang Yang9,Jinlin Hou10,Qing Xie11,Caiyan Zhao12,Lunli Zhang13,Xiaorong Mao14,Tong Sun15,Lang Bai16,Fuchun Zhang17,Jinglan Jin18,Yingren Zhao19,Maorong Wang20,Wen Xie21,Yingjie Ma22,Jun Quan23,Xuebing Yan24,Ping An25,Feng Lin26,Jidong Jia27,Xiaoxuan Hu28,Zuojiong Gong29,Jie Wu30,Yongping Chen31,Zhansheng Jia32,Minghua Lin33,Guiqiang Wang34,Yueyong Zhu35,Yingjun Zhang*,36,Hongming Xie36,Lin Luo36,Qingyun Ren36,Rui Huang1 and Lai Wei*,37 Author information Journal of Clinical and Translational Hepatology 2020;8(3):255-261DOI:10.14218/JCTH.2020.00031 Abstract Background and Aims:Emitasvir is a new type of hepatitis C virus(HCV)nonstructural protein 5A(NS5A)inhibitor,and the data of phase 2 trial has shown emitasvir-sofosbuvir to have good safety and tolerance.We conducted this phase 3 trial to further verify the efficacy and safety.Methods:We evaluated the antiviral activity and safety of a 12-week regimen of emitasvir phosphate(100 mg)combined with sofosbuvir(400 mg)once daily in non-cirrhotic patients with genotype 1 HCV infection.The primary endpoint was a sustained virological response at 12 weeks(SVR12)after the end of treatment.Results:Of the 362 patients enrolled in the trial,39.8%were male,99.2%had HCV genotype 1b,0.8%had genotype 1a and 79.8%were treatment-naïve.The average age was 47.2 years.All patients completed the treatment and follow-up.All 3 patients with genotype 1a achieved SVR.Two genotype 1b treatment-naïve patients experienced virologic relapse.The rate of SVR12 was 99.7%(358/359),and SVR24 was 99.4%(357/359)in genotype 1b.Overall,36.2%had resistance-associated substitutions(RASs)in NS5A and 98.3%had RASs in NS5B at baseline.The RASs at baseline had no effect on the rates of response.Serious adverse events were reported in 16 patients and were not related to emitasvir-sofosbuvir.Most adverse events did not require therapy.Conclusions:The 12 weeks of treatment with emitasvir-sofosbuvir was a highly efficient and safe treatment for a wide range of patients with HCV genotype 1b infection without cirrhosis,who had not been treated or who had been treated with interferon-based regimen previously.

Guidelines for the Prevention and Treatment of Chronic Hepatitis B(version 2022)

To facilitate the achieving of the goal of“eliminating viral hepatitis as a major public health threat by 2030”set by the World Health Organization,the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases(both are branches of the Chinese Medical Association)organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China(version 2022).With the support of available evidence,this revision of the guidelines focuses on active prevention,large scale testing,and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B related disease burden.

96-Week Treatment of Tenofovir Amibufenamide and Tenofovir Disoproxil Fumarate in Chronic Hepatitis B Patients

Background and Aims:Tenofovir amibufenamide(TMF)is a novel phosphoramidated prodrug of tenofovir with nonin-ferior efficacy and better bone and renal safety to tenofovir disoproxil fumarate(TDF)in 48 weeks of treatment.Here,we update 96-week comparison results.Methods:Patients with chronic hepatitis B were assigned(2:1)to receive either 25 mg TMF or 300 mg TDF with matching placebo for 96 weeks.The virological suppression was defined as HBV DNA levels<20 IU/mL at week 96.Safety was evaluated thoroughly with focusing on bone,renal,and metabolic pa-rameters.Results:Virological suppression rates at week 96 were similar between TMF and TDF group in both HBeAg-positive and HBeAg-negative populations.Noninferior efficacy was maintained in the pooled population,while it was first achieved in patients with HBV DNA≥7 or 8 log10 IU/mL at baseline.Non-indexed estimated glomerular filtration rate for renal safety assessment was adopted,while a smaller decline of which was seen in the TMF group than in the TDF group(p=0.01).For bone mineral density,patients receiv-ing TMF displayed significantly lower reduction levels in the densities of spine,hip,and femur neck at week 96 than those receiving TDF.In addition,the lipid parameters were stable after week 48 in all groups while weight change still showed the opposite trend.Conclusions:TMF maintained similar efficacy at week 96 compared with TDF with continued superior bone and renal safety profiles(NCT03903796).

CD55 Variant Associated with Pegylated-interferonαTherapy Response in HBeAg-positive Chronic Hepatitis B Patients

Background and Aims:Only a small percentage of chronic hepatitis B(CHB)patients effectively respond to treatment with pegylated-interferon alpha(PegIFNα)or nucleos(t)ide analogues(NUCs).We aimed to detect the correlations of complement regulators-associated single-nucleotide polymorphisms(SNPs)with treatment response of hepatitis B e antigen(HBeAg)-positive CHB patients.Methods:A total of 1,763 HBeAg-positive CHB patients were enrolled,894 received PegIFNαfor at least 48 weeks and were followed up for 24 weeks,and 869 received NUCs for 104 weeks.For each patient,nine SNPs in genes encoding for complement regulators were determined and genotyped.To assess the cumulative effect of numerous SNPs,a polygenic score(PGS)was utilized.The correlations of SNPs and PGS with the levels of combined response(CR)and hepatitis B s antigen(HBsAg)loss were also investigated.Results:In PegIFNα-treated patients,an intronic SNP of CD55,rs28371597,was strongly related to CR,and the CR rate in rs28371597_GG genotype carriers was only approximately half that of rs28371597_GT/TT genotype carriers(20.29%vs.37.10%,p=2.00×10^(−3)).A PGS incorporating CD55_rs28371597 and two additional SNPs,CFB_rs12614 and STAT4_rs7574865,which had been considered as predictors for PegIFNαtreatment response before,was strongly correlated with the levels of CR(ptrend=7.94×10^(−6))and HBsAg loss(p-trend=9.40×10^(−3))in PegIFNα-treated patients.In NUCs-treated individuals,however,none of the nine SNPs were shown to be significantly linked to CHB treatment response.Conclusions:CD55_rs28371597 is a promising biomarker for predicting CHB patients’responsiveness to PegIFNαtherapy.The updated PGS may be used for optimizing CHB treatment.

Guidelines for the Prevention and Treatment of Chronic Hepatitis B(Version 2022)

To facilitate the achieving of the goal of“eliminating viral hepatitis as a major public health threat by 2030”set by theWorld Health Organization,the Chinese Society of Hepatology together with the Chinese Society of Infectious Diseases(both are branches of the ChineseMedical Association)organized a panel of experts and updated the guidelines for prevention and treatment of chronic hepatitis B in China(version 2022).With the support of available evidence,this revision of the guidelines focuses on active prevention,large-scale testing,and expansion of therapeutic indication of chronic hepatitis B with the aim of reducing the hepatitis B–related disease burden.

HBsAg Loss with Peg-interferon Alfa-2a in Hepatitis B Patients with Partial Response to Nucleos(t)ide Analog:New Switch Study

Background and Aims:Hepatitis B surface antigen(HBsAg)loss is seldom achieved with nucleos(t)ide analog(NA)therapy in chronic hepatitis B patients but may be enhanced by switching to finite pegylated-interferon(Peg-IFN)alfa-2a.We assessed HBsAg loss with 48-and 96-week Peg-IFN alfa-2a in chronic hepatitis B patients with partial response to a previous NA.Methods:Hepatitis B e antigen(HBeAg)-positive patients who achieved HBeAg loss and hepatitis B virus DNA<200 IU/mL with previous adefovir,lamivudine or entecavir treatment were randomized 1:1 to receive Peg-IFN alfa-2a for 48(n=153)or 96 weeks(n=150).The primary endpoint of this study was HBsAg loss at end of treatment.The ClinicalTrials.gov identifier is NCT01464281.Results:At the end of 48 and 96 weeks'treatment,14.4%(22/153)and 20.7%(31/150)of patients,respectively,who switched from NA to Peg-IFN alfa-2a cleared HBsAg.Rates were similar irrespective of prior NA or baseline HBeAg seroconversion.Among those who cleared HBsAg by the end of 48 and 96 weeks'treatment,77.8%(14/18)and 71.4%(20/28),respectively,sustained HBsAg loss for a further 48 weeks.Baseline HBsAg<1500 IU/mL and week 24 HBsAg<200 IU/mL were associated with the highest rates of HBsAg loss at the end of both 48-and 96-week treatment(51.4%and 58.7%,respectively).Importantly,extending treatment from 48 to 96 weeks enabled 48.3%(14/29)more patients to achieve HBsAg loss.Conclusions:Patients on long-term NA who are unlikely to meet therapeutic goals can achieve high rates of HBsAg loss by switching to Peg-IFN alfa-2a.HBsAg loss rates may be improved for some patients by extending treatment from 48 to 96 weeks,although the differences in our study cohort were not statistically significant.Baseline and on-treatment HBsAg may predict HBsAg loss with Peg-IFN alfa-2a.

Efficacy and Safety of All-oral,12-week Ravidasvir Plus Ritonavir-boosted Danoprevir and Ribavirin in Treatment-naive Noncirrhotic HCV Genotype 1 Patients:Results from a Phase 2/3 Clinical Trial in China

Background and Aims:Ravidasvir(RDV)is a new generation pangenotypic hepatitis C virus(HCV)NS5A inhibitor,with high barrier to baseline resistance-associated species.This is the first phase 2/3 study conducted in China's Mainland confirming the efficacy and safety of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks in treatment-naive noncirrhotic patients with genotype 1 infection in a large population.Methods:In this multicenter,randomized,doubleblinded,placebo-controlled phase 2/3 trial(NCT03362814),we enrolled 424 treatment-nafve,noncirrhotic adult HCV genotype 1 patients.All patients were randomized at 3∶1 ratio to receive a combination of RDV 200mg once daily plus ritonavir-boosted danoprevir 100mg/100mg twice daily and oral ribavirin 1000/1200mg/day(body weight<75/≥75 kg)(n=318)or placebo(n=106)for 12 weeks.The primary end-point was the rate of sustained virologic response 12 weeks after the end of treatment,and the safety was evaluated and compared between treatment and placebo groups.Results:The overall rate of sustained virological response at 12 weeks after treatment is 99%(306/309,95%,CI:97%-100%)under per protocol set analysis.All patients harboring baseline NS5A resistance-associated species in the treatment group(76/76,per protocol set)achieved sustained virological response at 12 weeks after treatment.No treatment-related serious adverse events were reported.Laboratory abnormalities showed mild or moderate severity(grade 1 and grade 2)in liver function tests.Conclusions:In treatment-na(i)ve,noncirrhotic HCV Chinese patients infected with HCV genotype 1,all-oral regimen of RDV+ritonavir-boosted danoprevir+ribavirin for 12 weeks was highly efficacious,safe,and well tolerated.

A Real-world Prospective Study of Mother-to-child Transmission of HBV in China Using a Mobile Health Application (Shield 01)

Background and Aims:The World Health Organization(WHO)Western Pacific Region set a target of eliminating mother-to-child transmission(MTCT)of hepatitis B virus(HBV)by 2030.To assess the feasibility of this target in China,we carried out an epidemiological study to investigate the status quo of MTCT in the real-world setting.Methods:One thousand and eight hepatitis B surface antigen-positive preg-nant women were enrolled at 10 hospitals.Immunoprophy-laxis was administered to infants.In addition,mothers with HBV DNA level>2,000,000 IU/mL were advised to initiate antiviral therapy during late pregnancy.A health application called SHIELD was used to manage the study.Results:Nine hundred and five of the enrolled mothers,with 924 infants,completed the follow-up.Birth-dose hepatitis B vaccine and hepatitis B immunoglobulin were received by 99.7%and 99.7%of infants,respectively,within 24 h after birth.There ;were 446 mothers who received antiviral therapy,including 72.3%of the mothers with HBV DNA level>2,000,000 IU/mL and 21.0%of the mothers with HBV DNA level<2,000,000 IU/mL.Eight infants were infected with HBV.The overall rate of MTCT was 0.9%.Birth defects were rare(0.5%among in-fants with maternal antiviral exposure versus 0.7%among infants without exposure;p=1.00).Conclusions:The MTCT rate was lower than the WHO Western Pacific Region elimina-tion MTCT target in this real-world study,indicating that a comprehensive management composed of immunoprophy-laxis to infants and antiviral prophylaxis to mothers may be a feasible strategy to achieve the 2030 WHO elimination goal.

Targeting cIAPs,a New Option for Functional Cure of Chronic Hepatitis B Infection?

Hepatitis B virus (HBV)infection causes a wide spectrum of liver diseases in more than 240million people worldwide (Ott et al.2012).Patients with chronic hepatitis B (CHB)may progress to HBV-related end-stage liver diseases,such as hepatic failure,cirrhosis or hepatocellular carcinoma (HCC)(Tang et al.2018).

Viral and Antibody Kinetics of COVID-19 Patients with Different Disease Severities in Acute and Convalescent Phases:A 6-Month Follow-Up Study

Coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),has spread rapidly around the world,posing a major threat to human health and the economy.Currently,long-term data on viral shedding and the serum antibody responses in COVID-19 patients are still limited.Herein,we report the clinical features,viral RNA loads,and serum antibody levels in a cohort of 112 COVID-19 patients admitted to the Honghu People’s Hospital,Hubei Province,China.Overall,5.36%(6/112)of patients showed persistent viral RNA shedding(>45 days).The peak viral load was higher in the severe disease group than in the mild group(median cycle threshold value,36.4 versus 31.5;P=0.002).For most patients the disappearance of IgM antibodies occurred approximately 4–6 weeks after symptoms onset,while IgG persisted for over 194 days after the onset of symptoms,although patients showed a 46%reduction in antibodies titres against SARS-CoV-2 nucleocapsid protein compared with the acute phase.We also studied18 asymptomatic individuals with RT-qPCR confirmed SARS-CoV-2 infection together with 17 symptomatic patients,and the asymptomatic individuals were the close contacts of these symptomatic cases.Delayed IgG seroconversion and lower IgM seropositive rates were observed in asymptomatic individuals.These data indicate that higher viral loads and stronger antibody responses are related to more severe disease status in patients with SARS-CoV-2 infection,and the antibodies persisted in the recovered patient for more than 6 months so that the vaccine may provide protection against SARS-CoV-2 infection.

Guideline of Prevention and Treatment for Chronic Hepatitis B (2nd Version)

This guideline is established to standardize the prevention,diagnosis and antiviral therapy of chronic hepatitis B(CHB).For other treatment regimens and methods involving CHB,please refer to relevant guidelines and consensuses.The Chinese Society of Hepatology,Chinese Medical Association(CMA)and the Society of Infectious Diseases,CMA organized relevant native experts to establish this Guideline of Prevention and Treatment for Chronic Hepatitis B(1st version)in 2005,and made the first revision in 2010.In the past 5 years,great progress has been made in the native and foreign fundamental and clinical research with respect to CHB,necessitating additional revision of this guideline.

3-year Treatment of Tenofovir Alafenamide vs.Tenofovir Disoproxil Fumarate for Chronic HBV Infection in China

Background and Aims:Tenofovir alafenamide(TAF)has similar efficacy to tenofovir disoproxil fumarate(TDF)but with improved renal and bone safety in chronic hepatitis B patients studied outside of China.We report 3-year results from two phase 3 studies with TAF in China(Clinicaltrials.gov:NCT02836249 and NCT02836236).Methods:Chinese hepatitis B e antigen(HBeAg)-positive and-negative chronic hepatitis B patients with viremia and elevated alanine aminotransferase were randomized 2:1 to TAF or TDF treatment groups and treated in a double-blind fashion for 144 weeks(3 years).Efficacy responses were assessed by individual study while safety was assessed by a pooled analysis.Results:Of the 334 patients(180 HBeAg-positive and 154 HBeAg-negative)randomized and treated,baseline characteristics were similar between groups.The overall mean age was 38 years and 73%were male.The mean HBV DNA was 6.4 log10 IU/mL.The median alanine aminotransferase was 88 U/L,and 37%had a history of antiviral use.At week 144,the proportion with HBV DNA<29 IU/mL was similar among the two groups,with TAF at 83%vs.TDF at 79%,and TAF at 93%vs.TDF at 92%for the HBeAg-positive and-negative patients,respectively.In each study,higher proportions of TAF than TDF patients showed normalized alanine aminotransferase(via the American Association for the Study of Liver Diseases and the China criteria)and showed loss of HBsAg;meanwhile,the HBeAg seroconversion rates were similar.Treatment was well-tolerated among the TAF patients,who showed a smaller median decline in creatinine clearance(−0.4 vs.−3.2 mL/min;p=0.014)and less percentage change in bone mineral density vs.TDF at hip(−0.95%vs.−1.93%)and spine(+0.35%vs.−1.40%).Conclusions:In chronic hepatitis B patients from China,TAF treatment provided efficacy similar to TDF but with better renal and bone safety at 3 years.

Baseline Characteristics and Treatment Patterns of the Patients Recruited to the China Registry of Hepatitis B

Background and Aims: Chronic hepatitis B virus(HBV)in-fection remains a major public health problem globally.Here,we describe the baseline characteristics and treatment pro-files of HBV-infected patients recruited to the China Registry of Hepatitis B.Methods: Inclusion criteria were patients with different stages of chronic HBV infection and complete key data.Exclusion criteria were patients with hepatocellular car-cinoma.The baseline clinical,laboratory and treatment pro-files were analyzed.Results: Finally,40,431 patients were included.The median age was 43 years,with 65.2%being men and 51.3%being positive for hepatitis B e antigen(HBeAg).The most common initial diagnosis was chronic hep-atitis B(81.0%),followed by cirrhosis(9.3%),inactive carrier of hepatitis B surface antigen(HBsAg)(6.7%),and immune tolerant phase of hepatitis B infection(3.0%).Among the 21,228 patients who were on treatment,88.0%,10.0%and 2.0%received nucleos(t)ide analogues(NAs),interferon or combination of NAs and interferon,respectively.The propor-tion of patients who received preferred NAs(entecavir or te-nofovir disoproxil fumarate)had increased from 13.5%in 2003 to 79.7%in 2016.Conclusions: We concluded that middle-aged men accounted for most of the patients with chronic hepatitis B in this cross-sectional study.About half of the patients were HBeAg-positive.NAs were the most com-monly used therapy,and use of the preferred NAs had steadily increased in the past decade.

Management Algorithm for Prevention of Mother-to-child Transmission of Hepatitis B Virus(2022)

The World Health Organization(WHO)has set the goal of eliminating hepatitis as a threat to public health by 2030.Blocking mother-to-child transmission(MTCT)of hepatitis B virus(HBV)is not only the key to eliminating viral hepatitis,but also a hot issue in the field of hepatitis B prevention and treatment.To standardize the clinical management of preventing MTCT of HBV and achieve zero HBV infection among infants,the Chinese Foundation for Hepatitis Prevention and Control organized experts to compile a management algorithm for prevention of MTCT of HBV based on the latest research progress and guidelines,including 10 steps of pregnancy management and postpartum follow-up,among which screening,antiviral treatment,and infant immunization are its core components.

Dynamics of neutralizing antibody responses to SARS-CoV-2 in patients with COVID-19: an observational study

Our understanding of the protective immunity,particularly the long-term dynamics of neutralizing antibody(NAbs)response to SARS-CoV-2,is currently limited.We enrolled a cohort of 545 COVID-19 patients from Hubei,China,who were followed up up to 7 months,and determined the dynamics of NAbs to SARS-CoV-2 by using a surrogate virus neutralization test(sVNT).In our validation study,sVNT IC50 titers and the neutralization rate measured at a single dilution(1:20)were well correlated with FRNT titers(r=0.85 and 0.84,respectively).The median time to seroconversion of NAbs was 5.5 days post onset of symptoms.The rate of positive sVNT was 52% in the first week,reached 100% in the third week,and remained above 97% till 6 months post onset.Quantitatively,NAbs peaked in the fourth week and only a quarter of patients had an estimated peak titer of>1000.NAbs declined with a half-time of 61 days(95%CI:49-80 days)within the first two months,and the decay deaccelerated to a half-time of 104 days(95%CI:86-130 days)afterward.The peak levels of NAbs were positively associated with severity of COVID-19 and age,while negatively associated with serum albumin levels.The observation that the low-moderate peak neutralizing activity and fast decay of NAbs in most naturally infected individuals called for caution in evaluating the feasibility of antibody-based therapy and vaccine durability.NAbs response positively correlated with disease severity,warning for the possibility of repeat infection in patients with mild COVID-19.

Expert Consensus on Diagnosis and Treatment of End-Stage Liver Disease Complicated with Infections

End-stage liver disease(ESLD)is a life-threatening clinical syndrome that markedly increases mortality in patients with infections.In patients with ESLD,infections can induce or aggravate the occurrence of liver decompensation.Consequently,infections are among the most common complications of disease progression.There is a lack of working procedure for early diagnosis and appropriate management for patients with ESLD complicated by infections as well as local and international guidelines or consensus.This consensus assembled up-to-date knowledge and experience across Chinese colleagues,providing data on principles as well as working procedures for the diagnosis and treatment of patients with ESLD complicated by infections.

A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells(TCR-T cells)against hepatocellular carcinoma

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma(HCC)are urgently needed.The common cytokine receptorγchain(γc)family cytokines such as IL-2,IL-7,IL-15 and IL-21 play fundamental roles in T cell development,differentiation and effector phases.This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy.The antitumor function of AFP-specific T cell receptor-engineered T cells(TCR-T)was augmented by exogenous IL-21 in vitro and in vivo.IL-21 enhanced proliferation capacity,promoted memory differentiation,downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation.A novel engineered IL-21 receptor was established,and TCR-T armed with the novel engineered IL-21 receptors(IL-21R-TCR-T)showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand.IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo.IL-21R-TCR-T exhibited a less differentiated,exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation.The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization.The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.