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

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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.