Status of clinical research in HCV-negative recipients undergoing kidney transplantation from HCV-positive renal allografts / 器官移植

Antiviral therapy for chronic hepatitis C virus (HCV) infection has entered the era of direct antiviral agent (DAA), and up to 95% of patients could be clinically cured. Under this circumstance, HCV infection has gradually changed from relative contraindication to surgical indication for kidney transplantation. However, at present, the number of kidney transplantation from HCV-infected donors or recipients has been rarely reported in China. The short-term follow-up data of HCV-negative recipients undergoing kidney transplantation from HCV-positive renal allografts in other countries have confirmed that DAA yields high cure rate and safety in the treatment of HCV infection, and recipients could obtain favorable short-term survival and allograft outcome. However, the long-term safety of HCV-infected kidney transplantation remains to be validated by clinical trials with large sample size and long-term follow-up. In this article, the virological clearance, allograft outcome and safety of DAA use in HCV-negative recipients undergoing kidney transplantation from HCV-positive renal allografts under the intervention of DAA were investigated, aiming to evaluate clinical safety and efficacy of this pattern of kidney transplantation and deepen the understanding of safe use of HCV-positive organs.

Interacciones farmacológicas entre antivirales y plantas medicinales / Pharmacological interactions between antivirals and medicinal plants

Resumen: Objetivo: Identificar las plantas medicinales que presentan interacciones farmacológicas con los fármacos antivirales. Materiales y métodos: Se realizó una revisión bibliográfica mediante la recolección de artículos en las bases de datos PubMed, Scielo, Google académico. Se recuperó información de cada una de las plantas estudiadas hasta mayo de 2018. Se confeccionó una ficha instructiva a partir de la información obtenida, se tuvo en cuenta su utilidad y actualidad. Resultados: El 57.9% de la información fue recuperada de Google académico. El 47.9% del total de estudios revisados se referían a estudios clínicos y el 27% fueron investigaciones realizadas en Cuba. Allium sativum L. (19.7%), Hypericum perforatum (7.8%) y Panax quinquefolius (7.6%) fueron las plantas que presentaron mayor número de estudios concernientes a interacciones con antivirales. Las acciones sobre el citocromo P450 y la glicoproteína-P fueron las principales responsables de la ocurrencia de interacciones entre las plantas medicinales y los antivirales. La curcumina metabolito secundario de la Curcuma longa L. mostró potencial actividad antiviral ante virus de inmunodeficiencia humana tipo 1 sin obtenerse resultados concluyentes. Conclusiones: Podemos concluir que a pesar de que las interacciones farmacológicas entre antivirales y plantas medicinales son escasas, cuando se presentan lo hacen, en su mayoría, en forma de alteraciones farmacocinéticas. Los antirretrovirales fueron los fármacos de este grupo más involucrados en interacciones con plantas de uso común como el ajo. Los resultados encontrados fueron contradictorios en ocasiones y no todos estaban basados en evidencias clínicas.

Abstract: Objective: To identify medicinal plants that show pharmacological interactions with antiviral drugs. Materials and methods: A literature review carried out through the collection of articles in the PubMed, Scielo, Google academic databases. Information retrieved from each of the plants studied up to May 2018. An information sheet was prepared based on the information obtained and taking into account its usefulness and topicality. Results: 57.9% of the information was retrieved from academic Google. 47.9% of the total studies reviewed referred to clinical studies and 27% were investigations carried out in Cuba. Allium sativum L. (19.7%), Hypericum perforatum (7.8%) and Panax quinquefolius (7.6%) were the plants that presented the highest number of studies concerning interactions with antivirals. Actions on cytochrome P450 and P-glycoprotein were mainly responsible for the occurrence of interactions between medicinal plants and antivirals. The secondary metabolite curcumin of Curcuma longa L. showed potential antiviral activity against human immunodeficiency virus type 1 without obtaining conclusive results. Conclusions: We can conclude that although the interactions between antivirals and medicinal plants are rather rare when they occur, they do so mostly in the form of pharmacokinetic alterations. Antiretroviral drugs are the drugs of this group most involved in interactions with commonly used plants such as garlic. The results found are not all base on clinical evidence and sometime they were contradictories.

Progress and perspective of potential anti-coronavirus activity of phenothiazines / 药学学报

Coronaviruses (CoVs) are associated with some mammalian infectious diseases, which have caused several outbreaks of respiratory system infectious diseases in recent years. There is no effective vaccine or approved drug treatment against coronaviruses, and the development of anti-coronavirus agents is an urgent priority. Phenothiazines are a class of antipsychotic drugs, which were found that they have some other biological activities, like promising antibacterial, antifungal, anticancer, antiviral, etc. They can be used for drug repurposing. This review summarizes current researches on the potential anti-coronavirus activity of phenothiazine, discusses the mechanisms and some research difficulties, and provides a foundation for developing anti-coronavirus drugs which use phenothiazine as the lead compound.

Research progress on the application of liver transplantation in HIV combined with HCV positive patients / 器官移植

With the advent of highly active antiretroviral therapy (HAART), acquired immune deficiency syndrome (AIDS) has gradually evolved from an incurable terminal disease to a controllable chronic disease. Due to the extended survival of AIDS patients, chronic renal failure and (or) chronic liver failure have become the main cause of death, and AIDS patients with chronic liver failure are constantly complicated with hepatitis C virus (HCV) infection. Human immunodeficiency virus (HIV) infection was previously considered as a contraindication for liver transplantation. With the deepening of medical cognition and improvement of surgical management experience, the quantity of HIV positive liver transplantation recipients has been steadily elevated and high long-term survival rate has been achieved. Nevertheless, the 3-, 5-, and 10-year survival rates after liver transplantation of HIV combined with HCV positive patients remain extremely low. In this article, the development of liver transplantation in HIV positive patients, the disease progression of HIV combined with HCV positive patients, and the treatment for the recurrence of viral hepatitis C after the operation were summarized.

Recent advances in the research of broad-spectrum antiviral agents / 药学学报

Viral infections have always threatened human health. Broad-spectrum antiviral agents (BSAs) can either target host proteins that are essential for viral replication, or act on multiple viruses or multiple genotypes of the same virus. More importantly, BSAs could reduce the possibility of drug resistance. From the perspective of medicinal chemistry, this review summarizes recent advances in the research of broad-spectrum antiviral drugs with privileged structures or targeting specific targets in the viral life cycle.

Progress on the discovery and development of anti-zika virus agents / 药学学报

Zika virus (ZIKV) is a kind of mosquito-borne flavivirus. ZIKV infection initially shows mild symptoms on patients, but will lead to severe neurological complications (such as Guillain-Barré syndrome) in the end. Meanwhile, pregnant women are sensitive to ZIKV, since the viruses may cause microcephaly. In 2015, after the epidemic in Brazil, ZIKV draws the public attention around the world because of its increased virulence and rapid dissemination. However, there is no approved specific anti-ZIKV drugs at present. This review summarizes progress on anti-zika virus drug research and provides prospects in this field.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population.METHODS: Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis.RESULTS: The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence.CONCLUSION: Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

Guidelines for the prevention and treatment of hepatitis C (2019 version) / 中华肝脏病杂志

In order to standardize and update the prevention, diagnosis and antiviral therapy of hepatitis C and to achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat by 2030, Chinese Medical Association, the Chinese Society of Hepatology, and the Society of Infectious Diseases organized relevant native experts in 2019 to revise the guideline for the prevention and treatment of hepatitis C (2019 version) based on the basic, clinical and prophylactic research progress of hepatitis C infection at home and abroad, combined with the present actual situation of our country, so as to provide an important basis for the prevention, diagnosis and treatment of hepatitis C.

Real-world study of paritaprevir/ritonavir-ombitasvir combined with dasabuvir for the treatment of chronic hepatitis C 1b genotype infection in China / 中华肝脏病杂志

Objective@#To evaluate the real-world safety and curative effect of ombitasvir combined with dasabuvir for the treatment of chronic hepatitis C 1b genotype infection in non-cirrhotic or compensated cirrhotic patients.@*Methods@#A real-world research method was adopted, and the research was conducted at three medical centers of mainland China. Non- cirrhotic or compensated cirrhotic patients with HCV genotype 1b infection who were initially treated with IFN/PEG-IFN-alpha combined with ribavirin, and ombitasvir combined with dasabuvir for 8 or 12 weeks were taken. Sustained virological response (SVR) and the incidence of adverse events during treatment and follow-up were evaluated after 12 weeks of drug withdrawal at OBV/PTV/r 25/150/100mg once daily and DSV 250mg, twice daily. Median and range were used for description of non-normally distributed data.@*Results@#80 cases of GT1b were included in this study. Of these 88.8% (71/80) were newly diagnosed, 12.5% (10/80) were compensated cirrhotic, 97.5% (78/80) received 12 weeks treatment, and 2.5% (2/80) received 8 weeks treatment. The rate of HCV RNA negative at EOT (end of treatment) was 100% (64/64). A total of 67 patients completed the treatment within 12 weeks, and 43 patients returned to the hospital for further consultations, and SVR12 was 100%(43/43). No patient discontinued the drugs because of an adverse event during treatment.@*Conclusion@#In the real world, Ombitasvir combined with dasabuvir for the treatment of chronic hepatitis C 1b genotype infection in China has 100% rates of EOT and SVR12 with well- tolerability and safety.

Guidelines for the prevention and treatment of hepatitis C (2019 version) / 中华肝脏病杂志

In order to standardize and update the prevention, diagnosis and antiviral therapy of hepatitis C and to achieve the World Health Organization's goal of eliminating viral hepatitis as a public health threat by 2030, Chinese Medical Association, the Chinese Society of Hepatology, and the Society of Infectious Diseases organized relevant native experts in 2019 to revise the guideline for the prevention and treatment of hepatitis C (2019 version) based on the basic, clinical and prophylactic research progress of hepatitis C infection at home and abroad, combined with the present actual situation of our country, so as to provide an important basis for the prevention, diagnosis and treatment of hepatitis C.

Determination of Hepatitis B Immunoglobulin Infusion Interval Using Pharmacokinetic Half-life Simulation for Posttransplant Hepatitis B Prophylaxis

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. This study established an individualized HBV prophylaxis protocol, through optimization of hepatitis B immunoglobulin (HBIG) administration, with application of simulative half-life (SHL). METHODS: This study involved five parts: Part 1 developed the SHL estimation method with 20 patients; Parts 2 and 3 assessed the SHL variability and developed a simulation model to apply SHL in 100 patients; Part 4 validated the simulation model in 114 patients, and Part 5 was a cross-sectional study on the current status of HBIG infusion intervals in 660 patients. RESULTS: In Part 1, infusion of 10,000 IU HBIG induced add-on rise hepatitis B surface antibody (anti-HBs) titer of 5,252.5 ± 873.7 IU/L, which was 4.4% lower than actual measurement. Mean SHL of 20.0 ± 3.7 days was 2.2% longer than actual measurement. In Part 2, the medians of the intra- and inter-individual coefficient of variation in SHL were 13.5% and 18.5%, respectively. Pretransplant HBV DNA load and posttransplant antiviral therapy did not affect SHL. In Part 3, a simulation model was developed to determine the interval of HBIG infusion, by using SHL. In Part 4, all 114 patients were successfully managed with regular HBIG infusion intervals of ≥ 8 weeks, and the interval was prolonged to ≥ 12 weeks in 89.4%, with a target trough anti-HBs titer ≥ 200 IU/L. In Part 5, 47.4% of our patients received HBIG excessively, at a target trough titer of 500 IU/L. CONCLUSION: SHL estimation using only clinically available parameters seems to be reliably accurate when compared with actual measurements. We believe that SHL estimation is helpful to establish a personalized HBV prophylaxis protocol for optimizing HBIG administration.

Influence of hepatic steatosis on the outcomes of patients with chronic hepatitis B treated with entecavir and tenofovir

BACKGROUND/AIMS: The influence of hepatic steatosis (HS) on chronic hepatitis B (CHB) is unclear. We evaluated the influence of the degree of HS, assessed using the controlled attenuation parameter (CAP) of transient elastography (TE), on treatment outcomes in CHB patients initiated on antiviral therapy. METHODS: A total of 334 patients who were initiated on entecavir or tenofovir between 2007 and 2016 with available TE results were recruited. RESULTS: Of the total study population, 146 (43.7%) patients had HS (CAP > 238 dB/m). Three-hundred-three patients (90.7%) achieved complete virological response (CVR) (hepatitis B virus DNA<12 IU/L), and 25 patients (7.5%) developed hepatocellular carcinoma (HCC). Among hepatitis B e antigen (HBeAg)-positive patients (n=172, 51.5%), 37 (21.5%) experienced HBeAg loss. On univariate analysis, CAP value was not associated with the probability of HCC development (P=0.380). However, lower CAP value was independently associated with higher probability of HBeAg loss among HBeAg-positive patients (hazard ratio [HR]=0.991, P=0.026) and with CVR achievement in the entire study population (HR=0.996, P=0.004). The cumulative incidence of HBeAg loss among HBeAg-positive patients was significantly higher in patients without HS than in those with HS (log-rank, P=0.022). CONCLUSIONS: CAP values were not correlated with HCC development in patients initiated on entecavir and tenofovir. However, CAP values were negatively correlated with the probability of HBeAg loss among HBeAg-positive patients and with CVR achievement.

Research progress of hepatitis C in 2018 / 中华肝脏病杂志

Up to now, all major direct-acting antiviral agents (DAAs) have been approved, pan-genotypic regimens are recommended globally, simple monitoring strategy is recommended. In 2018, hepatitis C research focused more on accessibility, rather than new regimens. With the joint efforts of government and social groups, more infected people are getting affordable treatment. In addition approval of DAAs from global pharmaceuticals, a variety of DAAs have been on the clinical trial and approved in our country, and more options are/will be available with clinical trials progress. Management of infected fetus, children, and pregnant women will attract researchers’ attention.

Perspectives of antiviral drugs used on influenza / 中华流行病学杂志

Antiviral drugs on influenza are important in the control program of influenza.Options for influenza treatment are currently limited to using the neuraminidase inhibitors (NAIs).Given limited effectiveness of NAIs and related resistance,there remains an urgent need for the development of influenza antiviral drugs that can improve the efficacy and provide low propensity of viral resistance.Several influenza-related antiviral drugs that are currently under the late-stage clinical trials all appear differently in the mechanism of action.It is hoped that when new antiviral drugs are licensed,care and outcomes of severe influenza cases will be improved.

Perspectives of antiviral drugs used on influenza / 中华流行病学杂志

Antiviral drugs on influenza are important in the control program of influenza.Options for influenza treatment are currently limited to using the neuraminidase inhibitors (NAIs).Given limited effectiveness of NAIs and related resistance,there remains an urgent need for the development of influenza antiviral drugs that can improve the efficacy and provide low propensity of viral resistance.Several influenza-related antiviral drugs that are currently under the late-stage clinical trials all appear differently in the mechanism of action.It is hoped that when new antiviral drugs are licensed,care and outcomes of severe influenza cases will be improved.

Safety and efficacy of DCV-based DAAs therapy for chronic HCV infection in China / 中华肝脏病杂志

Objective@#To evaluate the efficacy and safety of DCV-based DAAs therapy for chronic HCV infected Chinese patients.@*Methods@#An open-label, non-randomized, prospective study was designed. Fifty-two patients with chronic HCV infection were enrolled. Among them, there was one patient after liver transplantation, 2 patients after kidney transplantation, 3 patients with hepatocellular carcinoma, and 4 patients with HBV infection. Thirteen cases with chronic hepatitis C (one compensated cirrhosis) who were negative for resistance-related variants [NS5A RAS (-)] of gene 1b and NS5A were treated with daclatasvir (DCV) + asunaprevir (ASV) for 24 weeks. Twenty-five cases of CHC (six compensated cirrhosis) with GT 1b, 2a, 3a, 3b, 6a were treated with DCV + SOF ± RBV for 24 weeks. 8 cases with decompensated cirrhosis of gene 1b and NS5A RAS(-) were given DCV + SOF + RBV regimen for 12 weeks. Six cases with decompensated cirrhosis, of gene 2a, 1b, 2a, 3a, 3b, were given DCV + SOF + RBV regimen for 24 weeks. HCV RNA, blood routine test, liver and kidney function, and upper abdominal ultrasound/MRI were measured at baseline, 4 weeks of treatment, end of treatment, and 12 weeks of follow-up. The incidence of adverse events and laboratory abnormalities during treatment were recorded. A t-test was used to compare the measurement data between two groups, and analysis of variance was used to compare the measurement data between multiple groups.@*Results@#Sixteen patients (100%) achieved SVR12 after treatment, with 0% recurrence rate. Rapid virological response (RVR) of the four treatment regimens were 76.92%, 54.17%, 87.50%, and 83.33%, respectively, and 32 patients achieved 100% virological response after the completion of treatment. The incidence of adverse events of chronic hepatitis C with cirrhosis and decompensated cirrhosis was 62.5% and 64.29%, respectively. The most common adverse event was fatigue in CHC (25.00%), and elevated indirect bilirubin in decompensated cirrhosis (42.86%). No serious adverse drug events, deaths or adverse reactions occurred.@*Conclusion@#DCV-based DAAs regimen is promising option for the treatment of HCV genotypes, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and HCV infection after liver/kidney transplantation in china. Above all, it has high SVR12 with good tolerability and safety profile.

Efficacy and safety of paritaprevir/ritonavir/ombitasvir combined with dasabuvir in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection: a randomized, double-blind, placebo-controlled study - China data / 中华肝脏病杂志

Objective@#To evaluate the safety and efficacy of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) 25/150/100 mg once daily combined with dasabuvir 250mg, twice daily in non-cirrhotic Chinese adult patients with newly diagnosed and treated chronic HCV genotype 1b infection. @*Methods@#A randomized, double-blind, placebo-controlled, multicenter phase 3 clinical trial was conducted in mainland China, Korea, and Taiwan.Safety and efficacy of OBV/PTV/r plus DSV administered for 12 weeks were evaluated in a newly diagnosed and treated (interferon alpha /pegylated interferon alpha) and ribavirin non-cirrhotic adults with chronic HCVgenotype 1b infection. Patients randomly received OBV/PTV/r plus DSV for 12 weeks (Group A), or placebo for 12 weeks (Group B) followed by an open-label phase of OBV/PTV/r plus DSV for 12 weeks. Sustained response (SVR12) rate obtained at 12 weeks and (SVR24) 24 weeks after discontinuation of treatment, and the incidence of adverse events and laboratory abnormalities after double-blind and open-label phase treatment were assessed. @*Results@#A total of 410 cases of Chinese patients were included and randomly assigned to group A and B (with 205 cases in each group) in a 1:1 ratio. The rates of SVR12 and SVR24 were 99% (95% CI: 94.8% - 99.8%) in the newly diagnosed patients in group A (205 patients) and the rates of SVR12 and SVR24 were 100% in treated patients (95% CI: 96.3% - 100%). Different baseline characteristics had no effect on SVR12 and SVR24 rates. Most of the adverse events occurred were mild, asymptomatic, and≥ 3 laboratory abnormalities during treatment were rare, including elevation of alanine aminotransferase (2 cases in double-blind stage A group), aspartate aminotransferase (Double-blind stage A (3 cases) and total bilirubin (1 case in open-label phase B group); however, those mild adverse events could be recovered after drug withdrawal or discontinuation. only1 person discontinued drugs due to adverse events (Group B, open-label phase). @*Conclusion@#The 12 weeks treatment course of OBV/PTV/r combined with DSV produced 99% ~ 100% rates of SVR12 and SVR24 in non-cirrhotic Asian adult patients with newly diagnosed and treated chronic HCV genotype 1b infection, and the tolerance and safety were good.

Re-treatment with peginterferon-ribavirin and direct antiviral agents of patients with chronic hepatitis C after failure of intensified treatment / 中华实验和临床病毒学杂志

Objective@#To explore the persistent viral response rate (SVR) in patients with refractory chronic hepatitis C after interferon (IFN) (peginterferon 360 μg qw) and ribavirin (PR) therapy failure. The SVR of patients with refractory chronic hepatitis C was improved by PR combined with direct antiviral agents (DAA) and proper extension of the course of therapy was applied.@*Methods@#Seventeen cases of refractory chronic hepatitis C after IFN(peginterferon 360 μg qw) and ribavirin therapy failure were given PR combined with DAA treatment. The side effects were observed and corresponding adjustments were made on drug dosage, and SVR was recorded.@*Results@#The 17 cases completed the whole course of treatment with PR combined with DAA for 24 weeks. All the 17 patients obtained rapid viralogical response (RVR) and SVR. After treatment, the SVR rate was 100% in patients including those with virologic relapse, retreated or previously non-responsive patients with refractory chronic hepatitis C. The adverse reaction of PR combined with DAA 24 weeks was generally mild.@*Conclusions@#The use of PR combined with DAA re-treatment in patients with refractory chronic hepatitis C can achieve SVR and shorten the treatment time. PR combined with DAA re-therapy is one of effective treatments to improve the rate of sustained viral response in patients with refractory chronic hepatitis C.

Influences of daclatasvir plus asunaprevir therapy on CD4+and CD8+T cell functions in patients with chronic hepatitis C / 中华微生物学和免疫学杂志

Objective To investigate the changes in CD4+and CD8+T cell functions in patients with chronic hepatitis C in response to daclatasvir plus asunaprevir therapy. Methods A total of 21 HLA-A2-restricted patients with chronic hepatitis C virus ( HCV) genotype 1b infection were enrolled in this study. All patients were treated with daclatasvir plus asunaprevir for 24 weeks. Peripheral blood samples were collected at baseline, 4 and 24 weeks post-therapy. CD4+and CD8+T cells were sorted and purified. Cytokines secreted by CD4+T cells were measured by flow cytometry. CD8+T cells were co-cultured with HCV cell culture ( HCVcc)-infected Huh7. 5 cells in both direct and indirect contact co-culture systems. The cytolytic and non-cytolytic functions of CD8+T cells were analyzed by measuring the levels lactate dehy-drogenase and cytokines in the supernatants of cell culture. Results The virological and biochemical re-sponse rates were 71. 43% (15/21) and 77. 78% (14/18) at 4 weeks post-therapy, respectively. Both rates reached 100% at 24 weeks post-therapy. Secretion of IFN-γ, TNF-α and IL-17 by CD4+T cells was significantly enhanced at 4 and 24 weeks in response to daclatasvir plus asunaprevir therapy. In contrast, IL-10 secretion by CD4+T cells did not change notably post-therapy. However, no significant differences in cy-tokine secretion were found between patients with and without virological response at 4 weeks post-therapy. Daclatasvir plus asunaprevir therapy increased the percentage of dead cells in direct contact co-culture system of CD8+T cells and HCVcc-infected Huh7. 5 cells at 4 and 24 weeks post-therapy. However, it did not af-fect the cytotoxity of CD8+T cells in indirect contact co-culture system. Moreover, IFN-γ expression in both direct and indirect contact co-culture systems was significantly increased at 4 and 24 weeks post-therapy. There was also a notable increase in the expression of TNF-α in direct contact co-culture system, while no remarkable change in TNF-α expression was detected in indirect contact co-culture system. No significant differences in cytolytic and non-cytolytic activities of CD8+T cells were found between patients with virologi-cal and without virological response at 4 weeks post-therapy. Conclusion Daclatasvir plus asunaprevir ther-apy achieves high clinical cure rate in patients with chronic hepatitis C. Inhibition of HCV replication con-tributes to the improvement of CD4+and CD8+T cell functions.

Preliminary observation of clinical efifcacy and safety of direct-acting antiviral agents for hepatitis C virus following renal ;transplantation / 器官移植

Objective To observe the clinical efficacy and safety of direct-acting antiviral agents(DAAs)in the treatment of hepatitis C after renal transplantation. Methods Six patients were complicated with hepatitis C virus(HCV) at 8 to 43 months after renal transplantation with a median time of 19 months. Prior to treatment, the virus load was detected from 4.03×103 to 8.18×107 IU/mL. Four cases were administered with tacrolimus(FK506)+mycophenolate mofetil(MMF)+prednisone(Pred), and the remaining 2 received cyclosporin(CsA)+MMF+Pred. The serum creatinine level was lower than 200μmol/L. The amount of urine and body weight remained stable. No severe mental irritation or trauma history wasreportedwithin6monthsbeforeantiviraltherapy.SixpatientsdidnotreceivegenotypetestofHCVbeforeDAAstherapy. Fourpatientswereadministeredwithsofosbuvir,1withsofosbuvir+ledipavirand1withsofosbuvir+daclatasvirfor12weeks. The complete blood cel count, serum transaminase level, creatinine level and blood concentration of immunosuppressive agents were measured each week and serum HCV RNA level was quantitatively detected every 4 weeks. Results Among 6 patients, 5 were negative for HCV at 4 weeks after DAAs therapy and obtained sustained virological response(SVR)after DAAs treatment. One case administered with sofosbuvir alone was positive for HCV after DAAs therapy. The patient was infected with genotype 5 HCV. After 12-week administration of sofosbuvir+daclatasvir, the patient was negative for HCV and obtained SVR. No significant changes were observed in complete blood cel count, serum transaminase level, creatinine level and blood concentration of immunosuppressive agents. Adverse reactions included evanescent eruption in 1 case and mild dizziness in 1 case. Conclusions DAAs treatment is an effective and safe approach for patients with stable renal function after renal transplantation. Combined use of sofosbuvir+daclatasvir is recommended as the optimal therapy.