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HIV Controllers Respond Better to Hepatitis B Vaccine


HIV positive natural controllers who maintain undetectable or low viral load without antiretroviral therapy (ART) are more likely to achieve adequate response to hepatitis B virus (HBV) vaccination and have improved survival, according to a study published in the August 21 edition of the open-access journal PLoS ONE.

Due to similar transmission routes, many people with HIV are also at risk for hepatitis B. Over years or decades chronic HBV infection can lead to advanced liver disease including cirrhosis and liver cancer. Since the advent of effective ART, liver disease due to hepatitis B or C has become a leading cause of death for people with HIV.

HIV care guidelines recommend that all HIV positive individuals should be vaccinated against HBV. But people with HIV have been shown to respond less well to HBV vaccination than HIV negative people, and those with advanced immune deficiency may not be able to mount an adequate response that can provide ongoing protection. Vaccine responsiveness among the small proportion of people with HIV who can control the virus without treatment has not been well studied.

Jason Okulicz from the Uniformed Services University of the Health Sciences and colleagues conducted a study of vaccine responsiveness in HIV positive people with and without good HIV control, both on an off ART, in the U.S. Military HIV Natural History Study.

The analysis of vaccine responsiveness included 44 HIV controllers: 2 "elite controllers" who had 3 or more undetectable viral load tests over a period of 12 or more months in the absence of ART, and 42 "viremic controllers" who had at least 3 viral loads <2000 copies/mL while off ART. The study also looked at 476 non-controllers who had not yet started HIV treatment when vaccinated against HBV and 284 non-controllers who were on suppressive ART during all vaccine doses.

Since HBV vaccine non-response has been associated with HIV disease progression in people with relatively well-preserved CD4 counts, the researchers also performed an analysis of progression to AIDS or death in relation to vaccine responsiveness. This analysisincluded a larger group of 143 controllers and 1566 non-controllers who had documented hepatitis B surface antibody (anti-HBs) levels regardless of vaccine timing relative to ART. HBV vaccine response was defined as hepatitis B surface antibody levels >10 IU/L after the last vaccine dose.

As is typical of military studies, most participants were men and race/ethnicity was diverse. The median age at HIV diagnosis was approximately 28 years. The HIV controllers, treatment-naive non-controllers, and non-controllers on ART had median CD4 cell counts of 614, 510, and 363 cells/mm3, respectively, at the time of HIV diagnosis, and 617, 425, and 524 cells/mm3, respectively, at the time of their last HBV vaccine dose. About half of participants in all groups received only 1 or 2 vaccine doses, while the other half had completed the full series of 3 injections.


  • Natural HIV controllers were significantly more likely to have positive HBV vaccine responses compared with ART-naive non-controllers (66% vs 37%, respectively).
  • However, HIV controllers and non-controllers on ART had similar response rates (66% vs 60%, respectively; not a significant difference).
  • HIV controllers were also more responsive than ART-naive non-controllers with viral load <10,000 copies/mL, but the sample size was too small to draw conclusions.
  • Among a subgroup of participants who received only 1 HBV vaccine dose, HIV controllers a large advantage over ART-naive non-controllers or non-controllers on ART, with response rates of 77%, 29%, and 34%, respectively.
  • Factors associated with vaccine response for HIV controllers compared to ART-naive non-controllers included controller status (odds ration [OR] 2.65), higher CD4 count at last vaccine dose (OR 1.28 for every additional 100 cells/mm3), and receiving all 3 vaccine doses (OR 0.56, or reduced likelihood of response).
  • The only factor significantly associated with response for controllers compared to non-controllers on ART was CD4 count at the last vaccine dose (OR 1.23 for every additional 100 cells/mm3) -- HIV controller status itself was no longer significant.
  • In the second analysis, HBV vaccine response rates were 79% for HIV controllers (82% for elite controllers and 79% for viremic controllers) compared to 62% for non-controllers (ART-naive and treated combined).
  • There was only 1 AIDS diagnosis and no deaths in the HIV controller group, compared with 165 cases of AIDS or death (11%) among non-controllers.
  • In the latter group, more events occurred among HBV vaccine non-responders than among responders (19% vs 6%, respectively).
  • Among HBV vaccine responders, the rate of AIDS or death was 0.14 per 100 person/years for HIV controllers compared to 0.98 per 100 person-years for non-controllers.
  • Among vaccine non-responders, the corresponding AIDS or death rates were 0 vs 4.11 per 100 person-years, respectively.
  • Time to AIDS or death was significantly longer for HIV controllers compared to non-controllers regardless of whether they were HBV vaccine responders or non-responders.

"HIV controllers have improved HBV vaccine responsiveness compared to treatment-naive non-controllers, but similar to those on viral load-suppressive HAART [highly active ART]," the study authors concluded. "Progression to AIDS or death can be predicted by HBV vaccine responder status for non-controllers, however these events are rarely observed in HIV controllers."

"Since HIV controller status is associated with favorable immunologic characteristics, enhanced functional immunity may play a role in the improved HBV vaccine seroresponses observed in this group," they elaborated in their discussion. "HIV infection in the absence of HAART has been shown to result in B-cell defects" and "[t]he absence of HBV vaccine response may be secondary to the inability of CD4+ T-cells to activate B-cells...," they added. "The observation that VL-suppressive HAART effectively closes the HBV vaccine response gap between non-controllers and HIC may be explained in part by the amelioration of these T- and B-cell defects during effective HAART."

"In summary, a positive response to HBV vaccine is important for HIV-infected individuals for prevention of liver-related morbidity due to HBV infection and may also have prognostic value for predicting HIV disease progression," they wrote.



JF Okulicz, O Mesner, A Ganesan, et al. Hepatitis B Vaccine Responsiveness and Clinical Outcomes in HIV Controllers. PLoS ONE. 9(8):e105591. August 21, 2014.