This is the first study that attempts to quantify the burden of and risks for hepatitis D in a national sample of hospitalized patients in the United States. In comparison with the hospitalized HBV only cohort, hospitalized hepatitis D patients were more likely male, Hispanic and from the Northeast region of the United States. In general, males were more likely than females to be injection drug users. Injection drug use has been a major transmission route of hepatitis D,[2,3,21] and in our study, we also found that injection drug use was more common in the hepatitis D cohort versus the HBV only cohort, potentially explaining the overrepresentation of males in the hepatitis D cohort. The disproportional distribution of hepatitis D in the Northeast may be due to an increased index of suspicion for HDV among clinicians in the Northeast region, resulting in increased screening of hepatitis B patients for HDV infection. Other possibilities were less clear; immigrants/foreign-born persons, who have been traditionally associated with having high HDV prevalence, were largely concentrated in the West region of the United States,[22,23] and syringe service programs were more likely to be available in the Northeastern states compared to many states in the South where they are illegal.
While we found that hepatitis D constituted a small percentage of the total hepatitis B hospitalizations, hepatitis D hospitalizations rates remained relatively constant between 2010 and 2018. In fact, we report that HBV only hospitalizations actually increased in the 2015–2018 period. This is consistent with a disturbing trend in the United States. Since the advent of widespread hepatitis B vaccination, cases of acute hepatitis B in the United States, as reported by the Centers for Disease Control and Prevention (CDC), have decreased each year; however, after 2010, this has stagnated and has even begun to increase slightly in recent years.[25,26] Stockdale et al. and Chen et al. reported in their systematic review and meta-analysis that the prevalence of HDV infections among HBsAg-positive individuals in the United States is estimated to be 5.9% and 7.2%, respectively.[2,3] However, a major weakness of Stockdale et al. and Chen et al. was that they largely relied on retrospective studies which suffer from the lack of routine hepatitis D testing after a diagnosis of hepatitis B. In contrast, a study utilizing the 2011–2016 National Health and Nutrition Examination Survey (NHANES) database, found that 33% of native born and 46% of foreign-born HBsAg-positive individuals living in the United States had positive anti-HDV serology. Regardless of which of those prevalence values was referenced, they all starkly contrasted the 0.6% prevalence of hepatitis D hospitalizations among total hepatitis B hospitalizations in our study. This suggested that, in practice, hepatitis D appeared to be vastly underdiagnosed in this country. With the development of new HDV antibody tests in recent years that have demonstrated high sensitivity and specificity,[27,28] we believe that routine of hepatitis D in all individuals with confirmed chronic hepatitis B will be beneficial.
We found no differences in mortality between hospitalizations of hepatitis D versus HBV only hospitalizations. A few prior studies have reported increased rates of mortality in patients with hepatitis D compared to those with HBV only, though the evidence there is not strong.[29,30] Another potential reason could be that the number of HDV hospitalizations was not large enough to appreciate the difference in mortality rate. In Figure S3, the case-fatality rate for HDV versus the HBV only cohort demonstrates the large range of case-fatality rates in the HDV cohort compared to the HBV cohort, mainly due to very low total number of deaths each year in the HDV cohort. Still, while there were no differences in mortality in our study, there were several significant morbidities and complications in the hepatitis D cohort. Liver failure, non-alcoholic cirrhosis, portal hypertension, ascites and thrombocytopenia were all more common in the hepatitis D cohort. However, there did not appear to be an increase in extra-hepatic complications in the conditions explored. This was largely consistent with the literature.[10,13] Thrombocytopenia, however, did appear to have been associated as a complication of hepatitis D. This finding was likely related to the higher rates of liver failure and non-cirrhosis in the hepatitis D cohort.
While there were no significant differences in complications and death among the pregnant persons and foetuses/neonates with hepatitis D versus HBV only, possibly due to a relatively small sample size, the proportion of pregnant persons in the hepatitis D cohort was less than one-third of those in the HBV only cohort. The age distribution between the two cohorts was similar, and although females were slightly less prevalent in the hepatitis D cohort, this difference was not proportional to the large difference in pregnancy proportions. This may suggest that hepatitis D could be adversely affecting fertility in women. Currently, there has been no published research on this question. In males, hepatitis B is known to increase the risk of infertility, reducing the quality of sperm and increasing the risk of varicoceles.[31,32] In females, Lao et al. reported increased frequencies of tubal and uterine factors involved in infertility in those with hepatitis B. It is possible that hepatitis D could be enhancing the effects of hepatitis B on infertility, or perhaps acting via an independent mechanism. On the other hand, the stark difference in pregnancy proportions between hepatitis D and HBV only cohorts may suggest that there were pregnant women in the HBV only cohort who have hepatitis D but have not been diagnosed with the disease. While hepatitis B is routinely screened in pregnant women, hepatitis D is not routinely tested for after a positive hepatitis B result. More research is needed to address this issue.
Although the rates of mortality were not significantly different between hepatitis D and HBV only cohorts, we further investigated the contributors of death within the hepatitis D cohort. As expected, older age (≥65 years) and alcoholic cirrhosis were both associated with mortality during hepatitis D-associated hospitalization. However, we did not expect that HIV and HCV co-infections would be insignificant in contributing to mortality. HIV infection in individuals with viral hepatitis, including hepatitis D, has typically been associated with severe complications such as increased rates of hepatocellular carcinoma and cirrhosis as well as increased mortality.[34–36] This is similar in the case of HCV co-infection.[37,38]
Due to the nature of the National Inpatient Sample database, a limitation of this study was the lack of standardization of diagnosis criteria. We rely on the professional judgement of clinicians in entering the most appropriate diagnostic codes. Another limitation is that method of diagnosis of HDV, whether anti-HDV antibody and/or HDV RNA was used, was not specified in the National Inpatient Sample, as such, the presence of HDV viremia could not be determined. However, while HDV viremia cannot be confirmed, there were clear increased clinical complications in the HDV cohort, suggesting that a large portion of the cohort may have had HDV viremia or have significant liver injury from past HDV infection. Additionally, there was the risk of miscoding as well. For this study, we made the assumption that any miscoded diagnoses and differing coding behaviours among clinicians would be randomly distributed and would not result in a statistical significance. Our study paves the way for further improved analysis in future with the next generation ICD-11 codes which better classify superinfection and co-infection of hepatitis D and make available options for diagnosis based on presence of HDV antibody versus detection of HDV RNA.
J Viral Hepat. 2022;29(3):218-226. © 2022 Blackwell Publishing