冠状病毒疫苗研究进展

进入21世纪以来,严重急性呼吸综合征冠状病毒(severe acute respiratory syndrome coronavirus, SARS-CoV)、中东呼吸综合征冠状病毒(Middle East respiratory syndromecoronavirus, MERS-CoV)及最新出现的严重急性呼吸综合征冠状病毒-2(severe acute respiratory syndrome coronavirus-2, SARS-CoV-2)等高致病性冠状病毒先后在人群中暴发流行,成为影响地区、国家乃至全球的重大公共卫生事件,研发特异性疫苗成为防控病毒流行的当务之急。本文综述了SARS-CoV和MERS-CoV疫苗的研究进展,望对SARS-CoV-2疫苗研制提供参考。     

冠状病毒感染患者消化系统表现的研究进展

目前可感染人类的冠状病毒(HCoV)共有7种,其中严重急性呼吸综合征冠状病毒(SARS-CoV)、中东呼吸综合征冠状病毒(MERS-CoV)和正在流行的2019新型冠状病毒(2019-nCoV)的危害性大、传染性强,这3种冠状病毒感染的患者多存在消化系统表现,故除呼吸系统外,消化系统可能是冠状病毒又一潜在的感染靶标。本文就SARS-CoV、MERS-CoV和2019-nCoV感染引发的消化系统症状及其相关研究进展加以综述,以加深临床医师对冠状病毒感染所致消化系统损害的认识,从而做到快速有效的诊疗。     

冠状病毒肺炎的流行趋势

目的通过对历史上发生的3次冠状病毒肺炎[严重急性呼吸综合征(SARS)、中东呼吸综合征(MERS)、新型冠状病毒肺炎(COVID-19)]流行数据的深入分析,探讨冠状病毒的传播特征与流行规律,探索疫情防控的关键节点,从而为公共卫生决策提供依据。方法针对3种冠状病毒的累计感染例数、新增感染例数、累计死亡例数与时间的关系进行描述统计与时间趋势分析,并按疫情的地区分布进行COVID-19与SARS亚组分析,进而比较不同地区疫情流行的异同点。采用SPSS 17.0对数据进行分析。结果3种冠状病毒肺炎中,COVID-19的传染速率最大,病死率最低(2.96%);MERS的传染速率最低,但病死率最高(30.49%)。COVID-19与SARS的流行规律相似,累计感染病例均是短期内迅速增长,累计感染曲线呈S型。而MERS主要以散发病例为主。结论冠状病毒的传染性与致死性存在着一定的负相关关系,即传染性越强致死性越低。冠状病毒的防控关键点是疫情早期切断传播途径可有效控制疫情扩散。     

新型冠状病毒疫苗的研究进展

COVID-19已经被世界卫生组织列为引起国际关注的突发公共卫生事件。目前尚没有该病的特效治疗药物。随着新型冠状病毒的不断传播以及变异,亟需寻求新型治疗措施来对抗这种病毒,积极研发新型冠状病毒疫苗十分必要。本文就目前新型冠状病毒疫苗的研究现状进行阐述、分类、分析及前景展望。     

干扰素联合利巴韦林治疗高龄慢性丙型肝炎患者1例

干扰素联合利巴韦林为目前公认的慢性丙型肝炎抗病毒治疗方案,但老年慢性丙型肝炎患者多合并有高血压病、心脏病和糖尿病等基础性疾病,耐受性差,限制了干扰素的应用。目前国内对老年人应用干扰素的报道不多,我们应用聚乙二醇干扰素联合利巴韦林治疗1例75岁慢性丙型肝炎患者,现报道如下。病例资料患者女性,75岁。反复肝功能异常1年于     

聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎疗效观察

目的评价聚乙二醇干扰素联合利巴韦林治疗慢性丙型肝炎的临床疗效。方法使用聚乙二醇干扰素α-2a(派罗欣)联合利巴韦林(800~1200mg/d)治疗58例慢性丙型肝炎患者,疗程48周,分别于治疗12周、24周和48周及治疗结束后24周评价疗效,并观察药物副作用。结果基因1型和非基因1型患者早期应答率分别为57.1%和76.7%(P>0.05),持续应答率分别为53.6%和80.0%(P<0.05);HCV RNA高水平组和低水平组之间持续应答率分别为56.3%和80.8%,具有显著性差异(P<0.05)。结论在慢性丙型肝炎患者的治疗中,基因1型患者疗效低于非基因1型,HCV RNA低水平组的疗效优于高水平组。     

干扰素联合利巴韦林治疗丙型肝炎肝硬化并溶贫危象1例报告

干扰素联合利巴韦林治疗丙型肝炎是目前公认的抗病毒治疗手段[1,2]。本文通过对1例丙肝患者应用干扰素联合利巴韦林抗病毒治疗后出现溶贫危象进行分析,并结合文献,复习报道于下。     

新型冠状病毒与神经退行性疾病的研究进展

<正>自从2019新型冠状病毒(COVID-19)成为全球大流行以来,威胁着全世界人民的生命和健康。在严重急性呼吸综合征冠状病毒(SARS-CoV)-2感染的急性期,已报道了一系列神经症状,从头痛[1]、谵妄[2]、认知障碍[3]到癫痫[4]、脑膜炎[5]和脑卒中[6]等,并且已有成像技术证明,COVID-19会对脑组织结构产生不可逆的影响[7]。除病毒感染急性期的神经系统症状外,SARS-CoV-2也对神经退行性疾病(NDs)产生了重要影响。     

人类高致病性冠状病毒起源和进化的简述

在2002年严重急性呼吸综合征暴发之前, 冠状病毒主要在动物之间流行, 在人群中仅引起轻微的上呼吸道症状。严重急性呼吸综合征冠状病毒(severe acute respiratory syndrome coronavirus, SARS-CoV)、中东呼吸综合征冠状病毒(Middle East respiratory syndrome coronavirus, MERS-CoV)和2019新型冠状病毒(2019 novel coronavirus, 2019-nCoV)所引起的肺炎暴发疫情促使研究人员对这些人类高致病性冠状病毒的来源和进化展开深入的研究。现对这3种人类高致病性冠状病毒起源和进化的最新研究进展进行综述和总结。     

Retreatment of high-dose interferon (5 MU daily) nonresponders with high-dose IFN + ribavirin

The treatment of chronic hepatitis C infection continues to evolve. Interferon (IFN) and ribavirin (RIBA) have become the mainstays of current therapy. The ideal dose and form of treatment of these two agents remains to be determined. An open label prospective trial of 5 MU of interferon daily plus ribavirin dosed according to weight was performed utilizing 40 patients, who were identified as being IFN nonresponders to 1 year or more of continuous IFN administered at a dose of 5 MU/day. Nineteen of the 40 subjects (47.5%) became HCV-RNA negative with normal serum ALT level when treated with the combination of IFN + RIBA. Thirteen of the 40 were sustained responders when reexamined after 6–12 months off active therapy. These results were achieved in a predominantly genotype 1 population (75%). This study suggests that the addition of RIBA to high-dose (5 MU daily) IFN can result in an increase in the number of cases experiencing both a short and sustained response to combination therapy.     

Serum B12 levels predict response to treatment with interferon and ribavirin in patients with chronic HCV infection

Summary. Vitamin B12 is stored in hepatocytes and inhibits hepatitis C virus (HCV) RNA translation. The implication of B12 in the setting of antiviral treatment is unknown. This study aims to retrospectively evaluate the discriminative efficacy of pretreatment B12 serum levels (s‐B12) on end‐of‐treatment response (ETR) in patients with chronic HCV. Ninety‐nine treatment naïve HCV patients, treated with interferon and ribavirin were studied. Serum B12 (s‐B12) was analysed in samples collected before treatment start. Pretreatment s‐B12 levels were correlated to ETR using univariate analysis. S‐B12 and clinical data were evaluated in a multivariate logistic regression model. Mean pretreatment s‐B12 was 331 pm in ETR and 260 pm in nonresponders (NR) (P = 0.012). In patients with s‐B12 levels ≤ 360 pm , 23 (31.5%) were NR and 50 (68.5%) had ETR. In patients with s‐B12 > 360 pm , one (3.8%) was NR and 25 (96.2%) had ETR (P = 0.0034). The results of the multivariate analysis were as follows: Pretreatment s‐B12 > 360 vs≤360 pm : OR 28.6 CI 2.31–354, P = 0.008. Fibrosis stage 3–4 vs 0–2: OR 0.29 CI 0.074–1.12, P = 0.068. Genotype 2/3 vs 1/4/5: OR 15.5 CI 2.87–83.9, P = 0.0012. Dose reduction vs no dose reduction: OR 0.21, CI 0.048–0.91 P = 0.034. Standard interferon vs pegylated‐interferon: OR 0.079, CI 0.0091–0.68 P = 0.019. Age and gender were not correlated to ETR. S‐B12 > 360 pm is independently correlated to ETR in HCV patients treated with interferon and ribavirin. This suggests that B12 is involved in suppression of viral replication during anti‐HCV treatment.     

Interferon alfa2a induction therapy in combination with ribavirin and amantadine for the treatment of naive patients with chronic HCV infection

Summary.  Pilot studies have suggested that the addition of amantadine to interferon (IFN) is effective against hepatitis C virus (HCV). Furthermore, IFN induction therapy seems to improve virological response rates. In this open, randomized, multicentre trial we compared safety and efficacy of a triple therapy comprising IFN α 2a, ribavirin and amantadine using high induction doses (6 MU IFN α daily for the first 6 weeks) against a therapy with standard IFN α dosages over the entire treatment period plus amantadine and ribavirin. A total of 158 naive patients with chronic HCV infection were randomized 1:1. Group A ( n  = 81): induction therapy with 6 MU IFN α daily for 6 weeks, followed by 6 MU three times a week (tiw) for 18 weeks and then 3 MU tiw until week 48. Group B ( n  = 77): standard therapy with 6 MU IFN α tiw for 24 weeks, followed by 3 MU until week 48. All patients received oral ribavirin (10 mg/kg/day) and amantadine (200 mg/day). The triple therapy was safe and well tolerated. There were no significant differences between the groups with respect to biochemical response rates. Groups A and B did not differ in virological response rates at the end of treatment (33% vs 35%) or at the end of the 6 month follow up period (37% vs 39%). We could not detect favourable effects on sustained virological response rates using induction therapy, in either genotype 1 or non-1 infected patients. In summary, induction therapy with 6 MU IFN α daily did not result in increased overall response rates compared with standard IFN α dosages of 6 MU tiw.     

Results of combination treatment with pegylated interferon and ribavirin in cirrhotic patients with hepatitis C infection.

BACKGROUND: The treatment of hepatitis C patients with advanced cirrhotic liver disease remains challenging and data on the outcome of treatment for this patient group is limited. RESULTS: Between September 2000 and August 2004, 61 cirrhotic patients started treatment with pegylated interferon and ribavirin (42 male, age range 29-69 years, 26 Asian). Forty-three (70%) patients were serum hepatitis C virus (HCV) RNA negative at the end of treatment and 24 (39%) achieved a sustained virological response (SVR). SVR was achieved for 35% (6/17) of patients with genotype 1, and for 39% (16/41) with genotype 3. Caucasians with genotype 3 demonstrated a higher cure rate (SVR 10/18 = 56%) than Asians (SVR 6/24 = 25%). Failure to achieve SVR was associated with lower platelet count, neutrophil count and albumin at baseline. Twenty patients suffered clinical or laboratory decompensation, five patients required hospitalization, and two patients died. Patients who experienced hepatic decompensation were older and had baseline characteristics associated with more advanced liver disease. CONCLUSION: The treatment of patients with advanced HCV is challenging, although many treated patients achieve SVR. Significant toxicity is experienced and there is treatment-related mortality. This balance of efficacy and toxicity needs to be considered before commencing treatment.     

Treatment of histologically mild hepatitis C virus infection with interferon and ribavirin: a multicentre randomized controlled trial

Current guidelines advocate no treatment for patients with histologically mild hepatitis C virus (HCV) infection. This was a UK multicentre randomized controlled trial comparing alpha-interferon (3 MU thrice weekly) + ribavirin (1000-1200 mg/day) for 48 weeks with no treatment in treatment naive, adult patients with histologically mild chronic HCV infection. The aim was to compare benefits, safety and efficacy of combination therapy with alpha-interferon 2b and ribavirin for 48 weeks with no treatment (current standard management) in this patient group. In the treatment group 32 of 98 (33%) patients achieved a sustained virological response (SVR). Patients infected with genotype 1 had a lower SVR than those infected with genotype non-1 (18% vs 49% P = 0.02). No patients who failed to achieve a 2-log drop in viral load at 12 weeks achieved SVR. Improvements in quality of life 24 weeks postcessation of therapy compared with baseline using the SF-36 questionnaire measures were observed in the treated group. For patients with mild HCV infection with viral genotype non-1, the results are sufficiently good to suggest that therapeutic decisions should no longer be biopsy-driven. For patients infected with genotype 1, a liver biopsy is still indicated as the low chance of SVR is outweighed by an unacceptable burden of side-effects. Patients who fail to respond by 12 weeks of therapy should have their treatment curtailed early.     

Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin

The aim of our study was to conduct a systematic review of studies evaluating antiviral therapy with pegylated interferon (PEG-IFN) alfa in combination with ribavirin for the management of recurrent hepatitis C after liver transplantation. Data sources included electronic databases and a manual search. Studies evaluating the efficacy and tolerability of PEG-IFN alfa with ribavirin in patients with recurrent hepatitis C were selected for inclusion. The information extracted from each of the selected publications included study design details, patient characteristics, treatment regimens and efficacy and tolerability end points. Nineteen studies including 611 patients were identified. PEG-IFN alfa-2b was used in 16 studies. The mean rate of SVR was 30.2% (range, 8-50%). Dose reduction and discontinuation of treatment were common in these studies (73% and 27.6%, respectively). The lack of an early virologic response (EVR) at 3months of therapy was the most frequently described predictive factor of nonresponse. Treatment discontinuation and dose reductions due to adverse events were frequent and possibly represent important obstacles to attainment of SVR. EVR at 3months of treatment should be considered an important predictor of treatment outcome.     

Combination therapy with interferon-alpha and ribavirin in patients with dual hepatitis B and hepatitis C virus infection

BACKGROUND: Patients with dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection have responded poorly to interferon (IFN) monotherapy. The purpose of the present paper was to assess the effect of combined IFN-alpha and ribavirin therapy in patients infected with both hepatitis B and C. METHODS: Thirty-six patients received 3 or 5 MU IFN-alpha-2b thrice weekly and oral ribavirin (800-1200 mg/day) for 24 weeks. All patients had positive hepatitis B surface antigen, antibody to HCV, and HCV-RNA. Before treatment, one patient had positive hepatitis B e antigen. Eighteen patients had positive HBV-DNA tested by Amplicor (Cobas Amplicor Monitor, Roche Diagnostics, Branchburg, NJ, USA), with a mean HBV-DNA level of 3.1 +/- 0.9 log copies/mL. Another 72 patients with HCV infection alone served as controls. RESULTS: Adverse events led to withdrawal in three patients receiving 5 MU IFN. Based on an intent-to-treat analysis, the biochemical response and serum HCV clearance rate at the end of 48 weeks follow up was similar in patients with dual infection and HCV infection alone (56% vs 72%; and 69% vs 71%, respectively). There was no significant difference in sustained HCV clearance rate between the 3-MU group (n = 13) and the 5-MU group (n = 23; 85% vs 61%). At the end of 48 weeks follow up, two (11%) of 18 pretreatment viremic patients had negative serum HBV-DNA (<200 copies/mL), while eight of those without pretreatment viremia had re-occurrence of HBV-DNA. CONCLUSIONS: Combination therapy with IFN-alpha and ribavirin was effective in achieving sustained HCV clearance in patients with dual HBV and HCV infection, comparable to those with hepatitis C infection alone. Combination therapy using 3 MU IFN-alpha seemed as effective as 5 MU, and was well tolerated in the study population. However, large-scale control trials are necessary to clarify these findings.     

Liver injury during highly pathogenic human coronavirus infections

The severe acute respiratory syndrome coronavirus 2 (SARS‐Cov‐2), the pathogen of 2019 novel coronavirus disease (COVID‐19), has posed a serious threat to global public health. The WHO has declared the outbreak of SARS‐CoV‐2 infection an international public health emergency. Lung lesions have been considered as the major damage caused by SARS‐CoV‐2 infection. However, liver injury has also been reported to occur during the course of the disease in severe cases. Similarly, previous studies have shown that liver damage was common in the patients infected by the other two highly pathogenic coronavirus – severe acute respiratory syndrome coronavirus (SARS‐CoV) and the Middle East respiratory syndrome coronavirus (MERS‐CoV), and associated with the severity of diseases. In this review, the characteristics and mechanism of liver injury caused by SARS‐CoV, MERS‐CoV as well as SARS‐CoV‐2 infection were summarized, which may provide help for further studies on the liver injury of COVID‐19.     

Combination therapy with interferon alpha and ribavirin for chronic hepatitis C virus infection in thalassaemic patients

Hepatitis C virus (HCV) infection is common in multi-transfused thalassaemic patients, and, in combination with transfusional iron overload, can result in progressive liver disease. Therapy with interferon-alpha causes a sustained loss of HCV in only 15–25% of patients, and there is as yet no established effective therapy for those who fail to respond. We have conducted a pilot study of combination anti-viral therapy for patients who failed to respond, or relapsed after an initial response to single-agent interferon-alpha. Patients were treated for 6 months with interferon-alpha 2b, given subcutaneously three mega units thrice weekly, together with ribavirin, orally 1 g daily. 11 patients were enrolled, their median age was 24.9 years. 8/10 evaluable patients had cirrhosis on biopsy, five were infected with HCV type 1 and all but one had initial HCV RNA titres > 10⁶ genomes/ml. Five patients (45.5%) had a sustained virological response with loss of serum HCV RNA for > 6 months after finishing therapy. There was no clear association between response to therapy and age, histology, HCV genotype, or HCV RNA titre. Transfusion requirements were significantly increased during the treatment phase, probably due to ribavirin-induced haemolysis, and this necessitated intensification of iron chelation therapy. Serum ferritin levels decreased significantly in those who responded. These results suggest that combination therapy is potent in clearing HCV infection, and may provide effective second-line therapy for thalassaemic patients who have failed to respond to interferon-alpha monotherapy.