Our study found a higher prevalence of HDV among IDUs with chronic HBV infection than has previously been reported in the United States, with 50% infected in 2005-2006. The majority of prior studies were performed in health-care settings, which may lead to an underestimation of HDV prevalence by excluding individuals with limited access to healthcare, given that such individuals may be at increased risk of acquiring HDV. The most recent estimate of HDV infection among HBsAg positive individuals comes from NHANES 2003-2004, in which participants who were HBsAg positive and anti-HBc positive were tested for HDAb. Only 1 of 28 (3.6%) were HDAb positive [26
], suggesting that the higher HDV prevalence may be concentrated in the IDU population.
Visiting a shooting gallery (a location where people gather to inject illegal drugs) emerged as the most important behavioral risk factor for HDV infection. Previous studies suggest that HDV is more efficiently spread parenterally than sexually [27
]. Our study corroborates these findings. However, there was evidence to suggest that high-risk sexual behavior might be important among infrequent or non-IDUs. More studies are needed to better understand the role of sexual transmission in HDV infection. However, our data are concerning as sexual transmission could facilitate the spread of HDV from IDUs to their sexual partners and subsequently to the general population.
Participants viremic for HDV had significantly higher levels of AST, and ALT, lower levels of albumin, and increased likelihood of a recent ER visit. These differences may be partially explained by HIV, which was present in all HDV viremic participants compared to only 31.1% of non-viremic participants. Progression to chronic HBV after acute infection is largely related to the immune status of the host. HIV infection is associated with greater likelihood of progression to HBV chronicity [28
], and this may be true for HDV as well. Unfortunately the cross-sectional nature of our study does not allow for determination of whether or not HIV infection predated HBV/HDV infection.
We found that participants who were exposed to HDV but were not viremic had significantly lower HBV viral load levels compared to both HDV- patients and HDV viremic patients. It is possible this group is mostly comprised of participants who were coinfected with HDV (they acquired both HDV and HBV at the same time, an event associated with clearance of both viruses the vast majority of the time) [29
]. The lowered HCV viral load among HDV viremic participants corroborates previous findings that HCV replication is inhibited in the presence of HDV [30
]. However, HCV viral load was not uniformly lowered among HDV viremic participants and in fact some had very high viral loads, as such careful monitoring of hepatitis viral levels is necessary in HDV patients.
One limitation of our study was the use of different HDAb testing methods at the two testing points. Based on the results of a previous study comparing HDAb RIA to ELISA in 1000 participants, we were able to adjust for the differences in sensitivity between the assays. The authors of the validation study noted that the discrepancy was predominately seen in patients with little or no active viral replication [24
]. This is most likely to affect patients who have already cleared both viruses because antibody titers wane over time and may eventually become undetectable. In this setting, antibody detection will depend on the sensitivity of the assay used. Patients with persistent HDV infection will maintain high levels of anti-HDV antibodies because of chronic antigenic stimulation [29
]. In this scenario, anti-HDV will be positive using both methods. Therefore we believe that the increase among chronic carriers is likely to be accurate. In previously exposed patients, some individuals negative by ELISA may have been positive by RIA. This would suggest that if incorrect, the observed increase HDAb prevalence in previously HBV-exposed individuals may actually be an underestimate. Furthermore, the difference in sensitivity of 8% observed between ELISA and RIA was seen in patients who were all HBsAg positive. This difference may be greater at lower antibody titers likely to be seen in HBsAg negative patients, meaning that even the adjusted ELISA estimate in the previously HBV-exposed participants may be an underestimate of the true HDV prevalence. A further limitation of our study is the use of behavioral data measured at time of testing rather than time of exposure. We cannot exclude the possibility that infection with HDV or HBV might change an individual's behavior, thus introducing a systematic bias into our results. Misclassification of this type would bias results towards the null; as such our behavioral risk factor analysis should be interpreted with this in mind.
Our findings underscore the importance of HBV vaccination, as it can prevent both HBV and HDV infections. Rates of HBV vaccination as measured by serology (HBsAb positive, cAb and sAg negative) were very low (2.9% in 1988-1989 and 5.0% in 2005-2006). As such efforts should be made to expand HBV vaccination coverage to at risk populations such as IDUs. It is possible that the low prevalence of HBsAb+ only serology is not entirely explained by decreased access to the vaccine in this population, but might also reflect decreased efficacy due to high rates of HIV [32
]. It is also possible that HBV infection predated vaccination for many in this cohort. Further research is needed to determine true levels of access and efficacy of the HBV vaccine in IDU populations.
Increasing prevalence of HDV among IDUs has potentially important clinical implications. HDV/HBV co-infection is generally more severe than HBV mono-infection in the acute setting, with a higher risk of fulminant hepatitis [29
]. In the setting of super-infection and chronicity, HDV has been shown to suppress HBV replication, potentially confounding clinicians because significant liver disease often occurs despite low or undetectable levels of HBV DNA [34
]. This can lead to delayed diagnosis, which is particularly concerning given the more aggressive nature of HBV/HDV chronic infection [4
]. In addition, oral nucleoside/tide analogue therapy, standard treatment for HBV, is ineffective in the presence of HDV, leaving high-dose prolonged interferon therapy as the only option [35
]. Our data suggest that all patients infected with HBV with a history of past or present IDU should be screened for HDV. Careful screening combined with further studies to better understand this change in epidemiology should be a priority in order to reduce the significant morbidity associated with HDV infection and to prevent the prevalence from rising further.