HDV screening in chronic HBV: An unmet need of growing importance
Authors: Abhishek Shenoy, Robert J. Fontana
Journal: Hepatology (2023)

HDV infection is an aggressive form of viral hepatitis associated with accelerated morbidity and mortality in patients with chronic HBV infection.1,2 HDV is a single-stranded, defective circular RNA virus whose replication inhibits HBV replication but enhances hepatic fibrosis progression and cancer risk. HDV requires the HBsAg envelope protein to enter hepatocytes through the sodium taurocholate co-transporting polypeptide receptor.2 Exposure to HDV can be determined by the detection of anti-HDV IgG or IgM antibodies, while active infection is defined by the presence of detectable HDV-RNA in the blood. HDV, like HBV, can be parenterally or sexually transmitted and may clinically present as acute coinfection with HBV that is usually self-limited in most patients (95%). In contrast, HDV superinfection in a patient with established chronic HBV leads to chronic HDV infection in 80%–90% of patients.2 HDV is considered a rare or "orphan disease" in the United States (ie, <200,000 patients) but screening for HDV among patients with chronic HBV remains woefully low at 5%–10% due to lack of physician education, awareness, and reliable diagnostic assays. In this issue of Hepatology, Gish et al1 present an interesting study on the estimated prevalence and clinical characteristics of adults with HDV-HBV coinfection in the United States. The authors defined HDV coinfection in the All-Payer Claims Database (APCD) by means of the presence of the International Classification of Disease (ICD) 9 or 10 diagnostic codes for HDV among patients who also had a code for HBV infection between 2014 and 2020. Using this methodology, the prevalence of HDV coinfection was 4.6% among the 144,975 adults with chronic HBV. Clinical risk factors for HDV coinfection included younger patient age, female sex, Black ethnicity, and patient geography. Patients with HDV coinfection demonstrated higher rates of decompensated liver disease and other comorbid illnesses, including HIV coinfection (30.9% vs. 8.1%), substance use disorders (28.7% vs. 13.2%), and sexually transmitted infections (18.7% vs. 2.2%). The 4.6% prevalence of HDV coinfection is similar to the estimates provided in other studies that used serological or other diagnostic methodologies (Table 1). TABLE 1 - Selected studies of HDV prevalence among patients with chronic HBV in the United States References Methodology (sample size) National referral center (NIH) National Institutes of Health (NIH) HDV prevalence among HBsAg + Comments Kushner et al3 Retrospective cohort study (2175) National VA Corporate Data Warehouse (1999–2013) Anti-HDV IgG antibody 3.4% - <50% patients had confirmed chronic HBV- Selection bias: only 8.5% of all patients with chronic HBV tested- Potential male sex bias (96%)- No HDV-RNA confirmation Pate et al4 Cross-sectional survey (21,832) National NHANES (2011–2016) Anti-HDV IgG antibody (DiaSorin) 42% - Representative of general US population including foreign born individuals- Only 113 patients with chronic HBV tested- High-risk populations excluded (homeless, incarcerated, institutionalized)- No HDV-RNA confirmation Nathani et al5 Retrospective cohort study (1444) Urban single-center (Mount Sinai New York) (2016-2021) Anti-HDV IgG antibody 6% - Single-center, retrospective urban population- Selection bias: only 13% of all patients with chronic HBV tested- No HDV-RNA confirmation Da et al6 Retrospective, cross-sectional cohort study (588) National Institutes of Health (NIH) (2000–2019) Anti-HDV IgG antibody, HDV-RNA or HDAg tissue stain confirmation 19% - Potential referral bias of national research center (NIH)- 80% of anti-HDV IgG (+) confirmed to have HDV-RNA Ferrante et al7 Retrospective, cross-sectional cohort (597) Multicenter HIV-HBV cohort (1996–2019) Anti-HDV IgG antibody (Diasorin), HDV-RNA 4.0% - Selection bias: all were HIV + co-infected enrolled in research network- Intravenous drug use only risk factor on multivariate analysis- 41% of anti-HDV IgG + were HDV-RNA +- All had HDV genotype 1 Gish et al1 Retrospective cohort study (144,975) National All-Payer Claims Database (APCD) (2014–2020) ICD-9/ICD-10 codes for HBV/HDV 4.6% - Insured population only- Discrepancies of pharmacy claims data- Zip code distribution and Geographic Prevalence Data- No laboratory confirmation of HDV diagnosis Abbreviations: APCD, All-Payer Claims Database; ICD, International Classification of Diseases; NIH, National Institutes of Health; NHANES, National Health and Nutrition Evaluation Survey. A major strength of this study was the large sample size available for analysis along with the demographic and geographic diversity. However, the authors did not perform a manual chart review to validate their case definition and confirm the diagnosis of HDV infection. In addition, the APCD database only captures data from those with medical insurance, which may lead to an underestimation of the true prevalence of HDV coinfection through exclusion of the uninsured. Furthermore, a remarkable 25% of all patients with HDV resided in either Brooklyn, New York or Chicago, Illinois. The disproportionate number of HDV cases from these 2 metropolitan areas may represent a larger number of immigrants from countries with a high rate of HDV coinfection (eg, Mongolia, Eastern/Western Africa, and Eastern Europe). Alternatively, these data may reflect differences in testing practices in those locations, leading to an overestimate of the true prevalence of HDV due to selection bias. WHO AND HOW TO SCREEN FOR HDV? IT'S COMPLICATED!! Worldwide, the estimated global prevalence of HDV is 4.5% but varies substantially by country.8 Currently, the European Association for the Study of the Liver (EASL) and Asian Pacific Association for the Study of the Liver (APASL) guidelines recommend universal screening of all patients with chronic HBV for HDV coinfection, while the American Association of the Study of Liver Diseases (AASLD) recommends targeted screening in high-risk groups.9 Universal screening for an infectious disease is recommended if there are (1) accurate, reliable, and validated diagnostic tests available; (2) safe and effective treatments or interventions to prevent (vaccinate) or improve the outcome following diagnosis; and (3) evidence that case detection and treatment may reduce disease transmission and associated morbidity and mortality. Over the past few years, the Centers for Disease Control (CDC) has largely abandoned targeted screening of high-risk individuals for HCV and HBV infection in favor of a simpler population and age-based strategy. Gish and others now advocate for universal screening of HDV coinfection among all patients with chronic HBV in the United States.1,2 However, it is important to remember that detection of HDV infection requires accurate, reliable, and standardized diagnostic tests before universal screening can be implemented. Currently, there is significant variability in the performance of anti-HDV antibody tests and none are Food and Drug Administration (FDA) approved for diagnostic testing.10 In addition, HDV-RNA assays have not yet been validated and have variable lower limits of quantification and detection. Finally, the sensitivity and specificity of HDV-RNA assays for isolates containing the 8 distinct genotypes of HDV have not been established.10,11 The optimal means to treat a patient with active HDV replication also remains unclear but is generally improving. Oral nucleos(t)ide analogs for HBV (ie, entecavir and tenofovir) do not lead to meaningful reductions in HDV-RNA levels or improvement in liver histology. In contrast, immunotherapy such as pegylated interferon alpha can partially suppress HDV replication in up to 30% of treated patients and lead to improved long-term survival.12 However, long-term pegylated interferon alpha is not well tolerated, nor currently FDA approved for this indication. Fortunately, recent progress has been made in our understanding of the HDV life cycle, leading to promising drug targets. Bulevirtide, a subcutaneously administered Sodium taurocholate co-transporting polypeptide inhibitor, reduces HDV-RNA and alanine aminotransferase levels in 56% of treated patients after 96 weeks of treatment.13 Although bulevirtide is generally well tolerated, it is not yet approved in the United States, and the optimal dose remains unclear. Oral prenylation inhibitors that block HDV replication, such as lonafarnib have also been tested, as well as pegylated interferon lambda and short interfering RNA approaches. Finally, on-treatment monitoring to look for HDV-RNA suppression is currently challenging due to the lack of an FDA-approved quantitative PCR–based assay, but several are in development. SO WHO SHOULD WE SCREEN FOR HDV INFECTION IN 2024? Anti-HDV serological testing helps identify those with acute versus chronic and resolved infections. Patients with acute HDV-HBV coinfection typically have anti-HDV IgM detectable for 1–3 months after exposure in the serum and HDV-RNA.2,10 In contrast, a detectable anti-HDV IgG serological test is evidence of either past or current infection, and active HDV infection is defined by detectable HDV-RNA in the blood (Figure 1). If one assumes that up to 4% of the 1.5 million Americans with chronic HBV are anti-HDV IgG positive, there may be as many as 50,000–60,000 individuals with active HDV-HBV coinfection that could benefit from treatment.FIGURE 1: Proposed algorithm to diagnose HDV-HBV coinfected patients. Anti-HDV serology testing is anticipated to identify 4% of the 1.5 million Americans with chronic HBV infection as having evidence of HDV exposure. Among those with HDV exposure, ~80% are anticipated to have detectable HDV-RNA, but prospective confirmatory studies using validated, quantitative PCR–based assays are needed. Overall, 50,000–60,000 Americans with active HDV-HBV coinfection may be eligible for anti-HDV therapy when it becomes available.The AASLD 2018 HBV Guidance recommends targeted screening for HDV infection in patients with high-risk HBV, including immigrants from countries where HDV is endemic, men who have sex with men, HIV coinfected patients, or patients who are actively using i.v. drugs.9 In addition, patients with chronic HBV with low HBV DNA levels but persistently elevated serum alanine aminotransferase should be screened for HDV as well as those with early cirrhosis, HCC, or awaiting liver transplant. However, widespread implementation of a targeted strategy for HDV screening has proven to be difficult. At Mount Sinai in New York City, only 13% of their patients with chronic HBV were screened for HDV between 2016 and 2022 (Table 1). Furthermore, 20% of those with confirmed HDV infection did not have an identifiable risk factor, highlighting the limitations of targeted screening.5 In Spain, with an estimated HDV seroprevalence of 9%, reflexive testing for anti-HDV antibodies from the same blood sample of newly diagnosed patients with HBV increased HDV detection rates from 7.5% to 93%.14 Additional studies of reflexive testing of HBsAg+ samples for HDV will be needed in both low and high-prevalence countries to help develop evidence-based and cost-effective screening practices. So, for now in 2024, we recommend that all patients with newly diagnosed HBV infection undergo testing for HCV, HDV, and HIV coinfection. In addition, it would be prudent to offer all adult patients with chronic HBV a one-time testing for HDV and annual testing for those with ongoing clinical risk factors for HDV acquisition. Lastly, the CDC should make HDV a reportable disease in the United States to help facilitate nationwide seroprevalence studies and identification of disease transmission in the community. With the advent of multiple promising anti-HDV therapeutics, there is an urgent unmet need to have highly reproducible, sensitive, and specific tests for HDV diagnosis that clinicians can use to risk stratify their patients with chronic HBV and help prioritize those with advanced fibrosis and active HDV replication for treatment.