The Treatment With Nucleoside Analogues in Combination With HBIG+GM-CSF+HBV Vaccine for Chronic Hepatitis B Patients With HBeAg Seroconversion: a Phase I/II, Single-blind, Randomized, GM-CSF-controlled Trial
试验速览
- 阶段
- 1 期
- 发起方
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- the rate of hepatitis B surface antigen (HBsAg) seroconversion
研究概览
简要总结
The host immunity has been generally recognized as the main factors to determine the outcome of chronic hepatitis B virus (HBV) infection; however, previous studies have shown that HBV-specific T cell and B cell function are exhausted in chronic hepatitis B (CHB) patients. Recently, It is suggested that hepatitis B surface antigen (HBsAg) may play a key role in the immune tolerance or immune exhaustion. Anti-HBV immune responses are partially recovered when patients achieved hepatitis B e antigen (HBeAg) seroconversion during antiviral therapy, and can be nearly recovered during HBsAg seroconversion. However, it is still difficult to achieve the ideal terminal, HBsAg seroconversion. For this reason, immunotherapy would be helpful to enhance the anti-HBV immunity and acquire higher HBsAg seroconversion. Here, the investigators propose a hypothesis that hepatitis B immune globin (HBIG)+granulocyte-macrophage colony-stimulating factor (GM-CSF)+HBV vaccine can enhance anti-HBV immune responses and improve HBsAg seroconversion in CHB patients who has achieved HBeAg seroconversion using nucleoside analogues treatment.
详细描述
The host immunity has been generally recognized as the main factors to determine the outcome of chronic hepatitis B virus (HBV) infection. Previous studies have shown that HBV-specific T cell and B cell function are exhausted in chronic hepatitis B (CHB) patients. Interestingly, these impaired T and B cell functions could be partially restored by antiviral treatment, but this recovery seemed to be uncompleted even if long-term HBV suppression and HBeAg seroconversion. Recently, several emerging evidences have indicated that HBV-specific immune responses could be nearly recovered after hepatitis B surface antigen (HBsAg) seroconversion. This phenomenon suggest that HBsAg may play a key role in the immune tolerance or immune exhaustion. Indeed, our recent studies have found that the patients with HBsAg seroconversion display an HBV-specific T and B cell responses. Thus, the amount of HBsAg may serve as a possible mechanism for evading the host immune response, while anti-HBs antibody and HBV specific-T cell responses provide protective immunity.
HBsAg was the Nobel prize discovery that identified HBV about 40 years ago; to this day HBsAg remains the hallmark of overt HBV infection. HBsAg synthesis during the HBV viral life cycle is complex, and typically occurs at the endoplasmic reticulum. The envelope open reading frame (ORF) contains pre-surface 1 (preS1), pre-surface 2 (preS2), and ORF-S domains and envelope proteins are generated from two HBV messenger ribonucleic acid (mRNA) transcripts, with subsequent translation resulting in small (ORF-S), medium (pres2 + ORF-S) and large surface envelope proteins (preS1 + preS2 + ORF-S). These are also known as large (L), medium (M) and small (S) surface proteins, respectively. However, HBsAg production far exceeds that required for virion assembly, and excess surface envelope proteins are secreted as non infectious filamentous or spherical sub-viral particles, which exceed virions by a variable factor of 102-105 and can accumulate up to concentrations of several hundred micrograms per milliliter of serum. These data suggested that sAg mainly derive from sub-viral particles, and the decline of serum HBsAg means reduction of covalently closed circular DNA (cccDNA) transcription and mRNA translation but not HBV replication. Recently, several studies suggest a new potential role of quantitative serum HBsAg in the prediction of virological response to antiviral therapy, at least in pegylated interferon (Peg-IFN) treated patients. In natural history of chronic HBV infection, HBsAg levels differ significantly during the 4 phases of HBV infection and decline progressively from immune tolerance (IT) (5 log IU/ml) to low replication (LC) (3 log IU/ml), while HBsAg/HBV-DNA ratios are significantly higher in LC as compared to all the others patients. These data suggested that the quantitative HBsAg may be a promising prognostic marker during the natural history of HBV-infection and during antiviral therapy. Thus, the loss of HBsAg and the development of anti-HBs antibodies (HBsAg-seroconversion) is the ultimate goal of anti-HBV therapy.
CHB patients would achieve HBV DNA replication inhibition, glutamic-pyruvic transaminase (ALT) normalization and hepatitis B e antigen (HBeAg) seroconversion after treatment with antiviral therapy. In addition, the antiviral immunity would be improved during the this process. However, it is difficult for these patients to clear HBsAg and reach the idea terminal. The major reasons are the presence of HBsAg and HBV-specific immunity was impaired. For this reason, immunotherapy would be helpful to enhance the anti-HBV immunity and acquire higher HBsAg seroconversion rate. The purpose of this study is to investigate whether and how immunotherapy ie. HBIG+GM-CSF+HBV vaccine improve the rate of HBsAg seroconversion. This study will also focus on the tolerance and safety of this treatment in CHB patients.
Participants in this study will be randomly assigned to one of two treatment arms:
Arm A: Participants will receive 48 weeks of nucleoside analogs (NAs) treatment combined with 24-week treatment with hepatitis B immune globin (HBIG)+granulocyte-macrophage colony-stimulating factor (GM-CSF)+HBV vaccine.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •chronic hepatitis B patients with HBeAg seroconversion (eAg negative and eab positive)
- •age 18-50, male or female
- •HBsAg positive for at least 6 months, quantitative HBsAg <1000 IU/ml (Abbott Diagnostic, Wiesbaden, Germany)
- •HBeAg positive CHB patients who have received NAs (lamivudine, adefovir dipivoxil, entecavir, alone or in combination) treatment and achieved HBeAg seroconversion (HBeAg-, HBeAb+), HBV DNA<40 IU/ml and ALT normalization and maintained for at least 6 months.
- •Urine pregnancy test is negative in gestational age female subjects before enrollment, who can take effective contraceptive measures and agree to contraception during treatment and follow-up period.
- •Enrolled subjects should understand and sign the informed consent and comply with the requirement of the research before study.
- •Enrolled subjects should agree not to participate in other studies, and not to accept other immunomodulatory therapy during the study. Other treatments such as corticosteroids should be informed timely
排除标准
- •Be allergic to HBIG, GM-CSF and HBV vaccine.
- •Coinfected with other virus. Any positive for anti-hepatitis A virus (HAV), anti-hepatitis C virus (HCV), anti-hepatitis D virus (HDV), anti-hepatitis E virus (HEV) and anti-HIV.
- •Advanced cirrhosis or Child-Pugh 7 scores or above.
- •Autoimmune thrombocytopenic purpura, coronary heart disease, cerebrovascular disease, hypertension, diabetes mellitus, high myopia, history of epilepsy.
- •Other causes of liver disease, such as autoimmune liver disease, alcoholic liver disease, nonalcoholic liver disease, drug-induced liver disease and other unknown causes of chronic liver diseases.
- •Associated with other serious organic disease, mental illness, including any uncontrolled urinary, respiratory, circulation, nervous, digestive, endocrine, spirit, immune system diseases and tumor.
- •Suspected liver cancer or alpha feto protein (AFP) > 100ng/ml.
- •Neutrophil count < 2.5×109/L, or hemoglobin < 100g/L, or platelet < 80×109/L.
- •Pregnant or lactating women.
- •Allergic constitution, allergy history for blood products, known allergy to experimental drugs.
- •Alcohol or drug addiction, drug use history evidence within one year before enrolled in the study.
- •Received immunosuppressive or other immune modulators (including thymosin) or systemic cytotoxic drug 6 months before enrolled in the study.
- •Incompliance during antiviral therapy.
- •Enrolled in other clinical trials at present, and possible to be against the treatment and observation index.
- •Unable or unwilling to provide informed consent or fails to comply with the requirements of the study.
- •Other serious conditions that may hamper clinical trials.
研究组 & 干预措施
Drug treatment
Drug: Given four times in week 0, 4, 12 and 24. At each time of treatment, the patients will be hospitalized and treated with 800 unit of HBIG intramuscularly at day 0, 1, 2, 3 and 4, then were treated with 75 μg of GM-CSF subcutaneously at day 2, 3, 4, 5 and 6, and finally were injected 20μg of HBV vaccine subcutaneously at day 6.
干预措施: Drug (Drug)
GM-CSF control
GM-CSF was given four times as control in week 0, 4, 12 and 24. At each time of treatment, the patients will be hospitalized and treated with GM-CSF intramuscularly or subcutaneously at day 2, 3, 4, 5, 6.
干预措施: GM-CSF control (Drug)
结局指标
主要结局
the rate of hepatitis B surface antigen (HBsAg) seroconversion
时间窗: At week 48
次要结局
- The rates of serum hepatitis B surface antigen (HBsAg) negative(At Baseline and at week 4, 12, 24, 36 and 48)
- the decreased levels of serum hepatitis B surface antigen (HBsAg)(At Baseline and at week 4, 12, 24, 36 and 48)
- Number of participants with adverse events as a measure of safety and tolerability(at baseline and up to week 48 week)
- The frequency of hepatitis B virus (HBV)-specific T cells(At baseline and at week 4, 12, 24, 36 and 48)
- The frequency of hepatitis B virus (HBV)-specific B cells(At baseline and at week 4, 12, 24, 36 and 48)
- liver hepatitis B surface antigen (HBsAg) levels(At baseline and week 48)
研究者
Fu-Sheng Wang
Research Center for Biotherapy
Beijing 302 Hospital