ACTG A5220: USING GM-CSF TO IMPROVE IMMUNE RESPONSE TO HEPATITIS B VACCINE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 预防乙肝病毒(HBV)感染对HIV感染者至关重要。接种乙肝疫苗已被证明在90%以上免疫能力强的成年人中产生保护性抗体水平。不幸的是，艾滋病毒感染患者对接种疫苗的反应很差，标准的乙肝疫苗接种策略的应答率从17.5%到56%不等。免疫反应差的原因很耐人寻味；疫苗因素和宿主免疫系统都可能起作用。在其他免疫受损的患者群体中，包括移植患者和透析患者，对乙肝疫苗的反应很差，但成功的策略通过增加剂量数量、增加剂量大小、使用佐剂进行疫苗接种以及在抗体效价下降时实施加强疫苗接种，改善了反应。粒细胞巨噬细胞集落刺激因子(GM-CSF)是一种免疫调节细胞因子，是理想的疫苗佐剂。 A5220是一项双臂、随机、II期、开放标签的试点研究，旨在评估在HIV感染和未感染的HIV感染和未感染的受试者中，使用和不使用GM-CSF作为佐剂的乙肝疫苗的有效性和安全性。研究持续时间为60周。48名受试者(每只手臂24名)将参加。研究人群为未接种乙肝疫苗的HIV感染者，年龄18岁，CD4+细胞数？200个/mm3，既往乙肝病毒和丙型肝炎病毒(HCV)感染血清阴性(在入境前30天内进行的乙肝核心总抗体、定性乙肝表面抗体、乙肝表面抗原和丙型肝炎病毒抗体检测必须为无反应[阴性])。受试者将根据他们筛查的血浆HIV-1RNA水平进行分层：1000拷贝/毫升或1000拷贝/毫升，并随机分为A组(第0天、第4周和第12周接种40微克乙肝疫苗)或B组(第0天、第4周和第12周接种40微克乙肝疫苗和250微克GM-CSF)。 这项研究的假设是，使用GM-CSF作为乙肝疫苗的佐剂将促进艾滋病毒感染者体内保护性滴度的乙肝表面抗体的形成。本研究的主要目的如下：1)评价40微克乙肝疫苗接种后第0、4、12周，联合或不联合GM-CSF的HIV感染者的16周定量抗-HBs滴度。2)评价GM-CSF作为乙肝疫苗佐剂的安全性。次要目标如下：1)评估每组受试者在16周时获得保护性免疫(定义为乙肝表面抗体和GT；10mIU/毫升)的比例。2)评价疫苗接种后4周和24周的乙肝表面抗体水平对免疫应答持续期的预测价值(定义为疫苗接种后48周的乙肝表面抗体10mIU/ml)。3)评价不同接种策略对HIV病毒载量的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prevention of hepatitis B virus (HBV) infection is essential to HIV-infected patients. Vaccination with hepatitis B vaccine has proven to yield protective levels of antibodies in greater than 90% of vaccinated immunocompetent adults. Unfortunately, HIV-infected patients respond poorly to vaccination, at rates ranging from 17.5% to 56% with standard HBV vaccination strategies. The reason for the poor immune response is intriguing; both vaccine factors and the host immune system may play a role. In other immunocompromised patient populations, including transplant patients and dialysis patients, response to hepatitis B vaccine is poor, but successful strategies have improved responses, by increasing the number of doses, increasing the dose size, using adjuvants to vaccine, and administering booster vaccinations when antibody titers wane. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is an immunomodulatory cytokine and is an excellent candidate to be a vaccine adjuvant. A5220 is a two-arm, randomized, phase II, open-label pilot study to evaluate the efficacy and safety of hepatitis B vaccine with and without GM-CSF as an adjuvant in HIV-infected, HBV-uninfected subjects na¿ve to HBV vaccination with CD4+ cell counts ?200 cells/mm3. The study is 60 weeks in duration. 48 subjects (24 per arm) will participate. The study population will be HIV-infected subjects na¿ve to HBV vaccination, ?18 years of age, with CD4+ cell counts ?200 cells/mm3, and seronegative for previous HBV and hepatitis C virus (HCV) infection (hepatitis B core total antibody [HBcAb total], qualitative hepatitis B surface antibody [HBsAb], hepatitis B surface antigen [HBsAg], and HCV antibody tests performed within 30 days prior to entry must be nonreactive [negative]). Subjects will be stratified by their screening plasma HIV-1 RNA levels: <1000 or ?1000 copies/mL and randomized to either Arm A (40 mcg HBV vaccine at day 0, week 4 and week 12) or Arm B (40 mcg HBV vaccine and 250 mcg GM-CSF at day 0, week 4, and week 12). The hypothesis of the study is that the use of GM-CSF as an adjuvant to hepatitis B vaccine will improve the development of a protective titer of HBsAb in HIV-infected subjects. The primary objectives are as follows: 1) To evaluate the week 16 quantitative HBsAb titers in HIV-infected subjects vaccinated with 40 mcg of hepatitis B vaccine at day 0, week 4, and week 12 with or without GM-CSF as an adjuvant. 2) To evaluate the safety of GM-CSF as an adjuvant to hepatitis B vaccine. The secondary objectives are as follows: 1) To evaluate the proportion of subjects in each arm who achieve protective immunity (defined as HBsAb >10 mIU/mL) at 16 weeks. 2) To evaluate the predictive value of HBsAb levels at 4 weeks and 24 weeks after completion of the vaccination series on the durability of response (defined as HBsAb >10 mIU/mL at 48 weeks after completion of the vaccination series). 3) To evaluate the effect of these HBV vaccination strategies on HIV viral load.