Transient Hepatitis B Surface Antigenemia After Hepatitis B Virus Vaccine in an HIV-Infected Patient

E ditor: Hepatitis B screening and vaccination are part of the standard of care in HIV-infected patients. The reasons for this recommendation are 2-fold. On the one hand, being infected with HIV is a risk factor for hepatitis B virus (HBV) infection as the two viruses share routes of transmission. On the other hand, the presence of HBV coinfection may influence the timing of highly active antiretroviral therapy (HAART) initiation and the HIV regimen chosen, as it must include agents with anti-hepatitis B activity. We present here a case that stimulated discussion regarding the interpretation of HBV serologies and the timing for HBV vaccination in the HIV-infected population. A 39-year-old African-American female was referred to our HIV clinic for initial evaluation after being diagnosed with HIV infection at the local health department. Bipolar disorder was her only significant past medical history. Three days earlier, as part of her initial HIV care at the health department, she received the first dose of Twinrix [a recombinant hepatitis A and hepatitis B vaccine containing inactivated hepatitis A virus (strain HM175) and noninfectious hepatitis B virus surface antigen (HBsAg)]. No hepatitis serologies were obtained prior to vaccination. This is consistent with local health department policy based on cost–benefit estimates.

At her first visit to our clinic, a hepatitis serology panel was obtained. The hepatitis A IgG, hepatitis B core IgG, hepatitis B surface IgG, and hepatitis C IgG were all nonreactive. Hepatitis B surface antigen was reactive. The serum HIV RNA level was 295 copies/ml, the CD4 count was 690 cells/mm³, and the complete blood count and comprehensive metabolic panel were within normal limits. The patient was contacted with the results, and she reported that she was asymptomatic. A serum HBV DNA obtained at that time was undetectable (<29 IU/ml). Since the laboratory results were not consistent with acute or chronic HBV infections, HBsAg was repeated upon her return to the clinic 4 weeks later, which was nonreactive. Clarification of the patient's HBV status was important as patients with HIV and HBV coinfection require special consideration regarding antiretroviral therapy and continued follow-up of liver status. For HBsAg testing our laboratory uses the ADVIA Centaur instrument and follows the manufacturer's recommendations for reporting a positive result. The ADVIA Centaur HBsAg assay is a sandwich immunoassay using direct, chemiluminometric technology and uses index values to determine reactivity. Samples with index values of 1.0 to 50.0 are weakly positive and are retested in duplicate prior to reporting the positive value.

A reactive HBsAg in the HIV-infected patient most often represents chronic HBV infection. However, in the reported case the hepatitis B core IGG was negative. Isolated hepatitis B surface antigenemia can occur early in hepatitis B infection or as we will describe as a postvaccination phenomenon. Based on the available information, this patient was most likely not infected by HBV but rather experienced a transitory HBs antigenemia following a Twinrix vaccine dose. While this phenomenon is well known in other settings, to our knowledge this is the first report in an HIV-infected patient. In our case, the relatively preserved CD4 count suggests that immunodeficiency did not play a role in the transient HBsAg.

Transient antigenemia following hepatitis B vaccination has been well described in neonates and end stage renal disease (ESRD) patients following both monovalent and bivalent (hepatitis A and B) vaccination. ¹ In neonates it is often the result of passive antibody transfer from the mother, which later disappears. In hemodialysis patients a study suggests that HBV immunization is the most common cause of detectable HbsAg, ² occurring in 13–31.6% of hemodialysis patients after immunization. ^3,4

Several factors have been proposed to explain the common occurrence of the phenomenon in this population: frequent screening per protocol, high dose and increased frequency of vaccination, advanced age, and prolonged time to neutralize HBsAg. ^{3 –5} Transient antigenemia after HBV vaccination has also been reported infrequently in blood donors and other healthy adults. ^{6 –11} In healthy adults HBsAg antigenemia is most likely to be found within 3 days after vaccination, although it can persist for up to 5 days. ^{8 –10} In ESRD patients those found to be HBsAg positive 2–7 days following vaccination were universally negative when retested 14–35 days later, but antigenemia can persist even at 28 days postvaccination according to some studies. ^2,3 In a recent review of mixed populations, transient antigenemia was reported to last between 3 and 21 days. ¹

Santana et al. ⁴ suggested that transient postvaccination HBs antigenemia in non-HIV patients may be a marker of no response to HBV vaccination. Thus, in his study only 16.6% of those with transient antigenemia responded to vaccination (i.e., anti-hepatitis B surface antibody titer≥10 mIU/ml) compared to 69% of those who did not have transient antigenemia. Others have suggested that the high sensitivity of HBsAg assays may also explain these cases of transient HBsAg positivity. ⁸ The phenomenon is not confined to one type or brand of vaccine, as it has been described with multiple vaccine formulations. ¹⁰ Many vaccine package inserts advise that serologies should not be obtained within 30 days of vaccination, but the warning is not universal for all HBV vaccines, as Twinrix does not include it. We suggest that all HBV vaccines available in the market should include a warning against HBsAg testing within 30 days postvaccination in any setting.

Although ideally hepatitis serologies should be obtained prior to vaccination in HIV-infected individuals, this practice is not economically feasible in many settings. Therefore, physicians evaluating new HIV patients should obtain information on recent vaccination before sending HBV serologies. In the case of our patient, we were aware of the immunization prior to her visit, although the timing of the vaccination was not defined or documented. As a result, additional expensive laboratory studies that were done to exclude active hepatitis B infection could have been avoided.