恩替卡韦抗乙型肝炎病毒剂量和疗效的研究

目的探讨恩替卡韦(ETV)治疗慢性乙型肝炎(CHB)的抗病毒活性,以找到一个合理的剂量用于今后大样本的临床试验。方法多中心、随机、双盲、安慰剂对照的临床试验,选择未经抗病毒治疗的CHB患者212例,按1:1:1的比例随机分为ETV 0.1 mg组69例,ETV 0.5 mg组72例,安慰剂组71例,治疗28d,并停药观察56 d。检测患者血清HBV DNA水平、乙型肝炎e抗原(HBeAg)和肝功能的变化。结果ETV组表现出明显的抗病毒活性,在治疗28 d后,用bDNA法检测HBV DNA水平,ETV 组中达到主要终点疗效(HBV DNA水平下降2个对数级或达测不出水平)的患者比例明显高于安慰剂组(分别为86%、93%、3%,P<0.01);0.5 mg/d ETV组的HBV DNA下降幅度>0.1 mg/d ETV组(P <0.01)。在56 d的停药观察期间,0.5 mg/d ETV组患者HBV DNA的反弹幅度<0.1 mg/d ETV组(P<0.01)。三组不良事件的发生率相当(ETV 0.1 mg组45%,ETV 0.5 mg组40%,安慰剂组42%)。无一例发生约物相关的严重不良反应。结论ETV组的抗病毒活性显著优于安慰剂,0.5 mg/d组的ETV的抗病毒活性比0.1 mg/d组更强且持久。

病毒接种剂量对HBV感染成年树鼩的影响

目的探讨不同病毒接种剂量对乙肝病毒(hepatitis B virus,HBV)感染树鼩进程的影响。方法分别给4组树鼩接种含101、102、104和108GE(genome equivalents)乙肝病毒的感染者血清,于不同时间点采集树鼩血清标本,应用实时荧光定量PCR(real-time fluorescence,PCR)检测血清HBV DNA浓度,用电化学发光免疫测定法(electrochemiluminescence immunoassay,ELICA)检测血清中HBV感染标志物,用临床生化分析仪测定谷丙转氨酶(alanine transaminase,ALT)水平。结果接种108GE HBV后树鼩体内HBV感染持续3周,接种104GE HBV后树鼩体内HBV感染延长至15周,接种101和102GE HBV后树鼩体内HBV感染可以存在9周。结论病毒接种剂量对HBV感染成年树鼩的进程有显著影响,中低剂量(101、102和104GE)接种利于树鼩体内HBV感染的维持。

老年丙型肝炎患者使用大剂量抗病毒治疗效果

目的:观察采用大剂量聚乙二醇干扰素ɑ-2a联合利巴韦林治疗老年丙型肝炎患者的临床疗效。方法:选取岳阳市第三人民医院院2010年4月至2013年4月间收治的丙型肝炎老年患者68例为研究对象,将其随机分为对照组和观察组,每组34例,对照组采用小剂量聚乙二醇干扰素ɑ-2a联合利巴韦林治疗,观察组患者采用大剂量聚乙二醇干扰素ɑ-2a联合利巴韦林治疗,比较两组患者的持续病毒学应答率,评价大剂量干扰素治疗丙型肝炎的临床价值。结果:观察组患者持续病毒学应答率明显高于对照组,差异具有统计学意义(P<0.05)。结论:大剂量聚乙二醇干扰素ɑ-2a联合利巴韦林治疗老年丙型肝炎患者可获得较高的持续应答率,提高临床治疗效率,值得临床推广应用。

大剂量丙种球蛋白联合抗病毒治疗在小儿病毒性脑炎中的治疗效果观察

就当前小儿病毒性脑炎治疗过程中,大剂量丙种球蛋白联合抗病毒治疗的临床效果进行观察和评估。方法:筛选2020年1月11日-2021年1月11日在我院的接受治疗的病毒性小儿脑炎患者共计50例,采取随机抽样分组的方式将其分为普通组和观察组,在普通组的治疗上,采取阿昔洛韦进行治疗,观察组采取阿昔洛韦结合大剂量丙种球蛋白治疗。针对两组患儿在经过治疗后头疼的停止时间、患儿恢复正常体温的时间,以及惊厥停止、意识恢复时间等方面进行结果的比对。若是最终获取的结果存在P<0.05,则代表比对结果存在较为显著的统计学差异,具备临床可比价值。结果:通过结果比对可知,相较于普通组而言,观察组的患儿在治疗后头疼的停止时间、患儿恢复正常体温的时间,以及惊厥停止、意识恢复时间等方面均有较为优异的结果,结果比对存在较为显著的统计学差异。结论:在当前针对小儿病毒性脑炎的治疗上,使用大剂量丙种球蛋白联合抗病毒治疗有较为出色的临床治疗效果,值得在临床应用普及和推广。

Co-infection of SENV-D among chronic hepatitis C patients treated with combination therapy with high-dose interferon-alfa and ribavirin

AIM： The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C （CHC） and response of both viruses to combination therapy with high-dose interferon-alfa （IFN） plus ribavirin remain uncertain and are being investigated.METHODS： Total 164 （97 males and 67 females, the mean age 48.1＋11.4 years, range： 20-73 years, 128 histologically proved） naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method.Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay （COBAS AMPLICOR HCV Test, version 2.0）. HCV genotypes la,lb, 2a, 2b, and 3a were determined by using genotypespecific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay （Quantiplex HCV RNA 3.0）. There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined.RESULTS： Sixty-one （37.2%） patients were positive for SENV-D DNA and had higher mean age than those who were negative （50.7＋ 10.6 years vs 46.6＋ 11.6 years,P = 0.026）. The rate of sustained viral response （SVR） for HCV and SENV-D were 67.3% （105/156） and 56.3% （27/48）, respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b （P〈0.001）, younger ages （P = 0.014）, lower pretreatment levels of HCV RNA （P = 0.019） and higher histological activity index （HAI） score for intralobular regeneration and focal necrosis （P= 0.037）. By multivariate analyses, HCV genotype non-lb, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR （odds ratio （OR）/95% confidence interval （CI）： 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively）. The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy （P = 0.04）.CONCLUSION： Coexistent SENV-D infection, apparently associated with higher ages, is found in more than onethird Taiwan Residents CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.

Apparent dose dependent antibody response in chickens immunized with orthopox virus antigens

Dose-dependent IgY antibody response to different amounts oforthopox virus （OPV） antigen has been studied in immunized chickens for two different OPV strains （vaccinia virus, 7.0× 10^6 PFU and cowpox virus, 9.2× 10^7PFU）. The antibody responses to different immunizations were tested and compared by indirect immunofluorescence antibody test. Our results, together with the literature, show that the antigen dose used for immunization plays an important role for the production of specific Abs. An increase in antigen concentration may achieve higher Ab titers but, dependent on the immunogenicity of OPV antigen, it can also lead to an immune depression. However, in this study we found that OPV played a positive correlation between antigen concentration and Ab-titer.

Immunogenicity and reactogenicity of a recombinant hepatitis B vaccine in subjects over age of forty years and response of a booster dose among nonresponders

AIM:The study was initiated to evaluate the reactogenicity and immunogenicity of a recombinant hepatitis B vaccine in age group >40 years and to study the response of a single booster dose in primary non-responders to the hepatitis B vaccination. METHODS:A total of 102 volunteers without markers of hepatitis B infection (negative for HBsAg,anti-HBc antibody, HBeAg and anti-HBs antibody) received 20μg of recombinant HB vaccine intramuscularly at 0,1,and 6 months.Anti HBs titers were evaluated by a quantitative Elisa kit at 90 and 210 days.A booster dose of 20μg HB vaccine was given after 6 months of the 3^(rd) vaccine dose to the 15 non- responders and anti-HBs titers were measured after i month. RESULTS:Seroprotection (anti-HBs GMT^3 10 IU/L) was achieved in 85.3 % (87/102) volunteers.The mean GMT titers of the vaccine responders was 136.1 IU/L.Of the seroprotected individuals,there were 32.4% (33/102) hyporesponders (anti- HBs titers <10-99 mIU/ml) and 52.9% (54/102) were responders (anti-HBs titers >100 IU/L).All the non-responders (15/15) responded to a single dose of the booster dose of recombinant HB vaccine and their mean anti-HBs antibody titers were more than 100.5 mIU/ml after the booster dose. CONCLUSION:Recombinant hepatitis B vaccine offers good seroprotection in the age group >40 years and has a good safety profile.A single booster dose after 6 months in primary non-responders leads to good seroprotective anti-HBs antibody titers.However,larger population based studies are needed to evaluate the role of a booster dose in selected group of non-responders and whether such an approach will be cost effective.

High-dose interferon-α2b induction therapy in combination with ribavirin for treatment of chronic hepatitis C in patients with non-response or relapse after interferon-a monotherapy

AIM： To evaluate the daily high-dose induction therapy with interferon-α2b （IFN-α2b） in combination with ribavirin for the treatment of patients who failed with interferon monotherapy and had a relapse, based on the assumption that the viral burden would decline faster, thus increasing the likelihood of higher response rates in this difficult-totreat patient group. METHODS： Seventy patients were enrolled in this study. Treatment was started with 10 NU IFN-α2b daily for 3 wk, followed by IFN-α2b 5 NU/TIW in combination with ribavirin （1 000-1 200 mg/d） for 21 wk. In case of a negative HCV RNA PCR, treatment was continued until wk 48 （IFN-α2b 3MU/TIW＋1000-1200 mg ribavirin/daily）. RESULTS： The dose of IFN-α2b or ribavirin was reduced in 16% of patients because of hematologic side effects, and treatment was discontinued in 7% of patients. An early viral response （EVR） was achieved in 60% of patients. Fifty percent of all patients achieved an end-oftreatment response （EOT） and d0% obtained a sustained viral response （SVR）. Patients with no response had a significantly lower response rate than those with a former relapse （SVR 30% vs 53%; P=0.049）. Furthermore, lower response rates were observed in patients infected with genotype la/b than in patients with non-1-genotype （SVR 28% vs7d%; P=0.001）. As a significant predictive factor for a sustained response, a rapid initial decline of HCV RNA could be identified. No patient achieving a negative HCV-RNA PCR at wk 18 or later eventually eliminated the virus. CONCLUSION： Daily high-dose induction therapy with interferon-α2b is well tolerated and effective for the treatment of non-responders and relapsers, when interferon monotherapy fails. A fast decline of viral load during the first 12 wk is strongly associated with a sustained viral response.

A dose-up of ursodeoxycholic acid decreases transaminases in hepatitis C patients

AIM:To examine whether a dose-up to 900 mg of ursodeoxycholic acid(UDCA) decreases transaminases in hepatitis C patients.METHODS:From January to December 2007,patients with chronic hepatitis C or compensated liver cirrhosis with hepatitis C virus(HCV)(43-80 years old) showing positive serum HCV-RNA who had already taken 600 mg/d of UDCA were recruited into this study.Blood parameters were examined at 4,8 and 24 wk after increasing the dose of oral UDCA from 600 to 900 mg/d.RESULTS:Serum alanine aminotransferase(ALT),aspartate aminotransferase(AST),and gamma-glutamyl transpeptidase(GGT) levels were signifi cantly decreased following the administration of 900 mg/d as compared to 600 mg/d.The decrease in ALT from immediately before the dose-up of UDCA to 8 wk after the dose-up was 14.3 IU/L,while that for AST was 10.5 IU/L and for GGT was 9.8 IU/L.Platelet count tended to increase after the dose-up of UDCA,although it did not show a statistically signifi cant level(P=0.05).Minor adverse events were observed in 3 cases,although no drop-outs from the study occurred.CONCLUSION:Oral administration of 900 mg/d of UDCA was more effective than 600 mg/d for reducing ALT,AST,and GGT levels in patients with HCV-related chronic liver disease.

Immunogenic and Protective Properties of the First Kazakhstan Vaccine against Pandemic Influenza А(Н1N1) pdm09 in Ferrets

This paper presents the results of a pre-clinical study of the immunogenicity and efficacy of an egg-derived, inactivated, whole-virion adjuvanted vaccine （Refluvac） on ferret models. For this purpose, groups of eight ferrets （6 to 7 months old） were injected with 0.5 mL of vaccine specimens containing 3.75, 7.5 or 15.0 μg of virus hemagglutinin. Administration was intramuscular and given either as a single dose or as two doses 14 days apart. All vaccine specimens manifested immunogenicity in ferrets for single （HI titer, from 51 ± 7 to 160 ± 23） and double （HI titer, from 697± 120 to 829 ± 117） administrations. To assess the protective effects of the vaccine, ferrets from the vaccinated and control groups were infected intranasally with pandemic virus A/California/7/09 （H1N1） pdm09 at a dose of 106 106/0.5 mL. Fourteen days post-infection, the ferrets inoculated with single or double vaccines containing 3.75, 7.5 or 15.0 ~g of hemagglutinin per dose showed no signs of influenza infection, weight loss, or body temperature rise, and no premature deaths occurred. The number of vaccinated ferrets shedding the virus via the upper airway, as well as the amount of virus shed after infection, was significantly reduced in comparison with animals from the control group. Based on our results, we suggest that a single vaccination at a dose of 3.75 or 7.5 μg hemagglutinin be used for Phase I clinical trials.

Over Exposure to Efavirenz Plasma Concentrations among Beninese HIV Patients Treated by A 600 mg Daily Dose

Therapeutic plasma concentrations of EFV （efavirenz） are between 1,000 ng/mL and 4,000 ng/mL. Concentrations below 1000 ng/mL are associated with higher risk of treatment failure, and concentrations above 4,000 ng/mL are associated with toxicity. The aim of the study was to appreciate EFV plasmas concentrations profile and the association between plasma levels and various characteristics in Beninese patients treated by a 600 mg standard daily-dose. Blood samples were collected and EFV plasma levels were measured by liquid chromatography coupled with mass spectrometry detection in HIV-infected patients receiving EFV in combination with other antiretroviral drugs for at least 14 days. Adverse effects occurring during treatment were collected through a questionnaire. An over-exposure to EFV among Beninese HIV patients were observed, with 46.4% of patients presenting EFV concentration above 4,000 ng/mL, although adverse effects were tolerated indicating that antiretroviral treatment is safe. The measurement of plasma concentration at the steady-state could contribute to early detection of treatment failure and adapt treatment in subjects presenting serious adverse effects within context of therapeutic drug monitoring.

Chronic Toxicity of a Novel Recombinant Human Granulocyte Colony-stimulating Factor in Rats

Objective To assess the severity and reversibility of the chronic toxicity of a novel recombinant human granulocyte colony-stimulating factor (rhG-CSFa) in rats and the dose-effect relationship.Methods A total of 100 Sprague-Dawley rats (equal numbers of male and female) were randomly divided into five groups (20 rats in each group):four groups were treated with rhG-CSFa at 500,100,10,1 μg/kg,respectively,and one group was treated with vehicle only to serve as the control.The rats were received subcutaneous injections of rhG-CSFa or vehicle daily for 13 weeks.During the course of the chronic toxicity study,the physical status,body weight,and food consumption were monitored.Half of the rats in each group (n=10) were sacrificed after the last rhG-CSFa administration,and the other half were sacrificed at five weeks after the last rhG-CSFa administration.Urinalyses,blood biochemistry,hematological analysis,histopathological examination,and immunological tests were performed for each of the rats.Results The hematological analyses revealed that the mean white blood cells count,neutrophils count,and neutrophils percentage were increased in male rats at the dose of 10 μg/kg or higher,and these were related with the biological activity of rhG-CSFa.Some small abnormalities were observed in the spleen of a few rats when used highest dose (500 μg/kg,a dosage of 200 folds higher than the normal clinical dosage),but these abnormalities were recovered within 5-week recovery period.No other rhG-CSFa-related abnormalities were observed in this chronic toxicity study.Conclusion No significant toxicity and immunogenicity are observed with rhG-CSFa administration to rats in the chronic toxicity studies.

White spot syndrome virus inactivation study by using gamma irradiation

The present study was conducted to investigate the effect of gamma irradiation on white spot syndrome virus （WS SV）. White spot syndrome virus is a pathogen of major economic importance in cultured penaeid shrimp industries. White spot disease can cause mortalities reaching 100% within 3-10 days of gross signs appearing. During the period of culture, immunostimulant agents and vaccines may provide potential methods to protect shrimps from opportunistic and pathogenic microrganisms. In this study, firstly, WSSV was isolated from infected shrimp and then multiplied in crayfish. WSSV was purified from the infected crayfish haemolymph by sucrose gradient and confirmed by transmission electron microscopy. In vivo virus titration was performed in shrimp, Penaeus semisulcatus. The LD50 of live virus stock was calculated 1054/mL. Shrimp post-larvae （1-2 g） were treated with gamma-irradiated （different doses） WSSV （10^o to 10^-4 dilutions） for a period of 10 days. The dose/survival curve for irradiated and un-irradiated WSSV was drawn; the optimum dose range for inactivation of WSSV and unaltered antigenicity was obtained 14- 15 kGy. This preliminary information suggests that shrimp appear to benefit from treatment with gamma- irradiated WSSV especially at 14-15 KGy.

Pneumocystis jiroveci pneumonia and pneumomediastinum in an anti-TNFαnaive patient with ulcerative colitis

We report the case of a 21-year-old man who was noted to have pneumomediastinum during an admission for an acute flare of ulcerative colitis. At that time, he was on maintenance treatment with azathioprine at a dose of 2.25 mg/kg per day, and had not received supplementary steroids for 9 mo. He had never received anti-tumor necrosis factor （TNF）α therapy. Shortly after apparently effective treatment with intravenous steroids and an increased dose of azathioprine, he developed worsening colitic and new respiratory symptoms, and was diagnosed with Pneumocystis jiroveci （carinii） pneumonia （PCP）. Pneumomediastinum is rare in immunocompetent hosts, but is a recognized complication of PCP in human immunodeficiency virus （HIV） patients, although our patient＇s HIV test was negative. Treatment of PCP with co-trimoxazole resulted in resolution of both respiratory and gastrointestinal symptoms, without the need to increase the steroid dose. There is increasing vigilance for opportunistic infections in patients with inflammatory bowel disease following the advent of anti-TNFα therapy. This case emphasizes the importance of considering the possibility of such infections in all patients with inflammatory bowel disease, irrespective of the immunosuppressants they receive, and highlights the potential of steroid-responsive opportunistic infections to mimic worsening colitic symptoms in patients with ulcerative colitis.

The effect of vaccination to dendritic cell and immune cell interaction in HIV disease progression

In this research paper, our main objective is to find out the meticulous role of activated dendritic cells （DCs） during the human immunodeficiency virus （HIV） infection process. DCs play a dual role by enhancing both HIV infection progression, as well as antiviral immune response. To explore the implications of these dual roles, we have formulated our mathematical model and analyzed the model by both analytical and numerical approaches. By using an impulsive differential equation, we have studied the effect of DC-based vaccination. Analytically we have determined the threshold value of drug dosage and dosing interval for optimum levels of injection. We have also investigated the effect of perfect adherence of drug dose on the immune cell count in extreme cases and observed that, systematic drug dose of the immune cells leads to its maximum level.