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Improving Detection of Hepatitis Delta Virus in the United States

Takeshi Saito, MD, PhD

Associate Professor of Medicine
Medicine, Division of Gastrointestinal and Liver Diseases
Keck School of Medicine of USC
University of Southern California
Los Angeles, California


Takeshi Saito, MD, PhD, has no relevant conflicts of interest to report.


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Released: August 20, 2021

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Hepatitis delta virus (HDV) is a defective virus that is known as a satellite of the hepatitis B virus (HBV) because its lifecycle is dependent on the hepatitis B surface antigen (HBsAg) for the formation of the viral envelope and virion assembly. Consequently, HDV infection occurs only in individuals with active HBV infection. Chronic HBV/HDV coinfection is the most aggressive form of viral hepatitis, resulting in accelerated progression of liver disease compared with HBV monoinfection. Individuals with chronic HBV/HDV coinfection typically develop cirrhosis in 5-10 years, whereas chronic HBV monoinfection commonly takes 40 years to progress to the onset of cirrhosis. Early diagnosis of HDV plays a critical role in mitigating disease burden.

Prevalence of HDV Among Patients Who Are HBsAg Positive
Since the implementation of the global HBV vaccine program in 1982, the prevalence of HBV infection among individuals born in the United States has declined. However, the overall prevalence of chronic HBV infection remains relatively unchanged due to migration from regions where HBV is endemic. Accordingly, most new HBV cases in the United States are now attributed to migration. Thus, HDV prevalence in the United States and any countries assimilating a large number of immigrants is expected to reflect the worldwide prevalence of HDV infection.

Based on recent epidemiological studies, it is now estimated that as many as 72 million people worldwide—or up to 10% of the HBsAg-positive population—are chronically coinfected with HBV and HDV, which is much higher than previously thought. Because the worldwide prevalence of HDV has a direct impact on US prevalence, it is likely that a considerable number of HDV carriers reside in the United States. To better understand the exact prevalence of HDV infection in the United States, more data are necessary to define the disease burden of HDV.

Recommendations on Screening for HDV
With only a minority of patients with chronic HBV infection being tested for HDV coinfection in the United States, the most critical milestone for identifying persons with HDV is increasing HDV awareness among healthcare workers. The low rate of HBV diagnosis is another barrier, with fewer than 20% of HBV infections being diagnosed and only 6% having received treatment in the United States.

Heterogeneity in HDV positivity across regions and subregions also must be considered. Regional disparity in HDV prevalence has been observed in the United States, partially due to local differences in racial and ethnic composition. Because people born outside the United States represent approximately 40% of all US HDV carriers, immigrants from endemic areas—such as Central Africa, Eastern Turkey, some countries in Asia and Eastern Europe, and the Amazonian region of Brazil—should be tested.

Lastly, a high prevalence of HDV infection has been noted among individuals with high-risk behaviors, such as IV drug users, men who have sex with men, and the HIV-coinfected population.

Accordingly, the implementation of focused screening strategies in high-risk populations and communities with a high density of immigrants from endemic regions will yield increased identification of HDV carriers.

What Steps Can Healthcare Professionals Take to Enhance HDV Screening and Diagnosis?
Higher rates of anti-HDV antibody positivity are noted among people who are HBsAg positive in hepatology clinic populations compared with the local general population. This finding likely mirrors the aggressiveness of HDV infection in the progression of liver disease. In fact, incidences of cirrhosis and hepatocellular carcinoma are 3 times higher with HDV infection than with HBV monoinfection. Therefore, HDV testing among HBsAg-positive populations with advanced liver disease is likely to be a high-yield strategy for identifying HDV carriers. However, diagnosis of HDV infection after the disease has progressed would not provide an opportunity for therapeutic intervention.

Although new drugs for HDV are on the horizon, the current standard treatment—peg interferon alfa—is contraindicated in patients with end-stage liver disease. Thus, obtaining a diagnosis early in the course of infection is a critical prerequisite for mitigating the disease burden of HDV. It follows that a minimum one-off HDV screen should be considered in all HBV-positive populations. No FDA-approved HDV test is available, but highly sensitive and specific 1-step, probe-based reverse transcription quantitative PCR testing, as well as antibody assays (immunoglobulins G and M), are available in commercial laboratories.

Why We Should Improve Detection of HDV
Los Angeles has not been known as a city with a high HDV prevalence, but the results of my group’s study in Southern California strongly highlight the importance of HDV awareness among healthcare professionals. Mongolia is an area of high HDV endemicity, and an estimated 30,000 Mongolian people live in the United States, with the largest population residing in California. Blood screening of more than 500 Mongolian people living in Southern California identified 10% with HBsAg reactivity. Of those, 41% had anti-HDV antibody, and 33% were HDV RNA positive. Of importance, 57% of people with HBV/HDV coinfection already had developed advanced fibrosis. Our results show that a large number of untested HDV-positive individuals are living in the United States, which emphasizes the importance of focused HDV screening of high-risk populations.

Your Thoughts
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