Advancing research, awareness, screening, and linkage to care to eliminate HDV in the U.S.

Abstract

HDV, which coinfects individuals living with HBV, is the most aggressive form of viral hepatitis. Compared with hepatitis B monoinfection, hepatitis delta is associated with more rapid progression to cirrhosis and an increased risk of liver cancer and death. Despite being a major contributor to hepatitis B-associated liver disease, hepatitis delta remains largely unknown to the general public, health care providers, and at-risk communities. Given the widespread lack of awareness and underdiagnosis of hepatitis delta in the US, the American Liver Foundation (ALF) and the Hepatitis B Foundation (HBF) convened a virtual Hepatitis Delta Roundtable Meeting on April 21 and 22, 2022. The Roundtable Panel included persons living with hepatitis delta, caregivers, liver disease specialists, primary care providers, state and federal public health professionals, and community-based organizations. The Panel identified several major challenges surrounding hepatitis delta, including a lack of awareness of hepatitis delta among the public and health care providers; complex risk-based testing protocols; a lack of accurate prevalence data; limited data on linkage to care; and inadequate communications among stakeholders. Potential strategies to address these challenges include improving and expanding education for different audiences; advocating for simplified protocols for hepatitis B screening with hepatitis delta reflex testing; expanding surveillance for hepatitis delta; requiring automated reporting and national notification; improving data sharing for research; and enhancing communications around hepatitis delta. The recent CDC recommendations for universal adult screening and vaccination against hepatitis B and the anticipated availability of new therapies for hepatitis delta present a unique opportunity to focus attention on this dangerous virus. The Roundtable Panel calls for urgent action to make significant progress in addressing hepatitis delta among individuals living with hepatitis B.

INTRODUCTION

HDV is the most aggressive form of viral hepatitis, accelerating the progression to severe liver disease and liver cancer in people living with HBV.^1–4 Despite its significant contribution to hepatitis B-associated liver disease, the HDV is largely unknown to the public and health care professionals, leaving many infected individuals undiagnosed.^5,6 First described in 1977,⁷ hepatitis delta is known as an incomplete virus because it requires the assistance of the HBsAg to be infectious in humans.^5,8 As such, hepatitis delta infects only people who are also infected with or at risk for HBV.^8,9 Approximately 4.5%–13% of people chronically infected with hepatitis B worldwide are coinfected with hepatitis delta,^6,10 with regions of highest prevalence, including Mongolia, Eastern Mediterranean countries, West and Central Africa, the Amazon basin, the Middle East, and South and East Asia.^5,6,10 In the US, estimates of the number of people living with hepatitis B who also have hepatitis delta range from 3% to 42%, depending on the analysis population.^6,11–15 Hepatitis delta is transmitted through sex with an infected partner, injection drug use, needle exposure, and hemodialysis. Household transmission can occur through sharing of items such as razors or toothbrushes. Unlike with hepatitis B, mother-to-child transmission of hepatitis delta is rare.^16,17 People may become infected with hepatitis B and delta at the same time (coinfection) or after first being chronically infected with hepatitis B (superinfection).^16,17 Treatments for HBV are not effective for hepatitis delta, necessitating complex management plans, including an increased need for liver transplantation.^18,19

The Roundtable Panel recognized that the recently updated recommendation from the Centers for Disease Control and Prevention (CDC) for universal vaccination against hepatitis B (for adults aged 19–59),²⁰ the draft recommendation from the CDC for universal hepatitis B screening of all U.S. adults, and the potential approval by the U.S. Food and Drug Administration (FDA) of treatments specific for hepatitis delta provide a unique opportunity to generate and build momentum around hepatitis delta prevention, diagnosis, and management. Increasing action around hepatitis delta will require a concerted effort by the viral hepatitis community at the federal, state, and community levels, in close collaboration with CDC, policymakers, and professional societies. To facilitate this, the Panel issued a call to action to identify unmet needs and suggest strategies to better support and engage the larger community around the prevention, diagnosis, and management of hepatitis delta.

PRIORITY FOCUS AREAS FOR THE HEPATITIS B AND HEPATITIS DELTA COMMUNITIES

Priority focus 1: generate accurate prevalence data

The prevalence numbers for hepatitis delta in the US are variable and are likely underestimates because of the low awareness of hepatitis delta, inadequate screening of HBsAg-positive populations, and the marked heterogeneity in assays.^4–6 The most recent U.S. estimates of hepatitis delta in HBsAg-positive persons range from 3% to 42%, depending on the analysis.^6,11–15 The capacity for hepatitis delta reporting also varies widely across state jurisdictions. The Panel noted that a system that relies on busy clinicians to report newly diagnosed cases is likely to fail. Because CDC currently does not require national notification of hepatitis delta cases, the few states that do collect prevalence data do not report these data to CDC.

The lack of uniformity in data collection across jurisdictions limits the utility of the collected data for community-level activities related to linkage to care and research. The Panel identified limitations in funding and resources for state-level surveillance activities as key barriers to incorporating hepatitis delta surveillance into Health Department’s existing programs. Limited prevalence data and underrecognition of cases hinder the ability to understand the clinical course of hepatitis delta and to appropriately plan for health care services for the affected populations. The paucity of seroprevalence data also affects communication with legislators.

Advocacy and community groups need prevalence data and information on effective treatments to make an impact on legislators.

ACTION ITEMS

Call on Centers for Disease Control and Prevention to develop a case definition for hepatitis delta to help generate accurate prevalence data:

• Survey state viral hepatitis coordinators to assess how many states are currently reporting hepatitis delta data to CDC. This can potentially be undertaken by the National Alliance of State and Territorial AIDS Directors (NASTAD).
• Incorporate hepatitis delta into existing statewide communicable disease, surveillance, and reporting systems.
• Provide funding to support the enhanced surveillance activities that will accompany the transition of hepatitis delta to a nationally notifiable and reportable disease.

Simplify reporting of cases:

• The Panel suggested that commercial and clinical laboratories should integrate automated reporting of testing results into existing state and local public health surveillance systems.

Consider alternative sources of prevalence data on hepatitis delta:

• Collaboration with harm reduction and refugee health programs to vaccinate against, educate about, and screen for hepatitis B and delta would also offer an opportunity to generate prevalence and outcomes data.

PRIORITY FOCUS 2: INCREASE AWARENESS

A key unmet need identified by all Panel members is the lack of awareness of hepatitis delta among persons living with hepatitis B and delta, the public, health care providers, public health professionals, and community-based organizations. Persons living with hepatitis B and delta, advocates, and even health care providers do not have ready access to basic information on the virus, such as its risk factors, the importance of timely diagnosis, and effective linkage to care. As a result, persons diagnosed with hepatitis delta often receive little or no information from their health care providers about the condition or appropriate clinical trials. Similarly, health care providers, particularly at the primary care level but also including specialists, may have little awareness of hepatitis delta, its dependence on hepatitis B for survival, or the need to test persons with hepatitis B for possible coinfection with hepatitis delta. This low awareness, compounded by the current lack of effective treatment options for hepatitis delta, may contribute to barriers to testing and appropriate linkage to care. Clinicians, particularly in primary care, are often wary of treating hepatitis B and need education to build their confidence in managing hepatitis B and referring patients with complicated diseases or hepatitis delta to specialists.

Historically, viral hepatitis has not received funding commensurate with its public health importance. With a continued lack of resources, public health professionals and community-based organizations may not be able to provide families with adequate educational materials on the different hepatitis viruses (A–E), including testing and treatment. Health care providers may participate in ECHO programs for education on viral hepatitis. These programs, however, have historically focused on hepatitis C and are aimed at primary care providers, whereas liver disease specialists are the main health care professionals caring for persons with hepatitis delta.

ACTION ITEMS

Create culturally sensitive educational resources on hepatitis delta for the public, primary care providers, and community organizations:

• Explain what hepatitis delta is and how it is prevented, diagnosed, and treated, and highlight the importance of lifestyle changes and linkage to ongoing care.
• Provide guidance for 2-way communication between providers and patients.
• Offer regularly updated information about clinical trials, liver transplantation opportunities, new therapeutic agents, and end-stage care.
• Underscore the risks associated with leaving hepatitis delta unmanaged, and the populations at highest risk for contracting the virus.
• Translate resources into multiple languages, particularly those of communities that are most heavily impacted.

Incorporate hepatitis delta information into hepatitis B ECHO programs for health care providers:

• The National Task Force on hepatitis B and other hepatitis B-focused ECHO hubs (Hepatitis B Foundation, Texas Heart Institute with Baylor St. Luke Medical Center, and other future hubs) could create a rapidly deployable hepatitis delta educational curriculum by incorporating comprehensive hepatitis delta education into all existing hepatitis B ECHO programs.

Increase funding for awareness programs:

• Through coordinated efforts, educate state, and federal agencies on the need to increase funding for viral hepatitis to support education, screening, vaccination, and public health services.
• Hold discussions between and among public health leaders, scientists, and advocates about how best to integrate hepatitis delta into public health and community programming.
• Use and expand existing advocacy tools to raise awareness among multiple stakeholders about a broad range of key considerations for eliminating viral hepatitis, including hepatitis delta.

PRIORITY FOCUS 3: SIMPLIFY SCREENING AND TESTING

The current risk-based screening guidelines for hepatitis B and delta from the American Association for the Study of Liver Diseases (AALSD)²¹ are complex and fail to take into account the fear and stigma that exist for persons with hepatitis B and delta. In addition, the risk-based approach presents a cost barrier to effective screening. Health insurance companies typically cover testing expenses only for the populations mentioned in the currently published risk-based testing guidelines for hepatitis B from the US Preventive Services Task Force (USPSTF).²² These guidelines do not mention hepatitis delta. Risk-based screening guidelines, inadequate clinician awareness of the importance of hepatitis delta screening, and the lack of an approved therapy for hepatitis delta in the US contribute to the low proportion of people living with hepatitis B, who are considered for hepatitis delta testing in both health care and community settings.^4,5,18

Many studies assessing seroprevalence of hepatitis delta in persons with hepatitis B do not use confirmatory PCR tests,^5,6 and standardized confirmatory tests are lacking.⁵ Currently used PCR assays may have variable testing accuracy across the different hepatitis delta genotypes.⁴ HDV reflex testing, which is automatically performed once an initially ordered HBV test is completed and positive for HBsAg using the same laboratory specimen and without intervention from an ordering physician, cannot be achieved without the availability of standardized, pangenotypic PCR assays. There can be no progress toward increasing hepatitis delta diagnosis without accurate serological and virological tests, and the lack of standardized testing presents one of the greatest challenges to addressing hepatitis delta in a meaningful way. The diagnostic markers vary for different stages of hepatitis delta infection, with some detectable only early in infection, and therefore frequently missed.²³ In addition, hepatitis delta genotyping is not routinely conducted in clinical practice because there is no clear utility.^21,24,25 Furthermore, commercial laboratories currently do not conduct reflex testing for hepatitis delta RNA in HBsAg-positive persons who test positive for hepatitis delta antibody. Studies have shown that simplified reflex testing can be effective for hepatitis delta,²⁶ achieving 99.4% hepatitis delta screening over a 12-year period for individuals who tested positive for hepatitis B infection. Similarly, anti-hepatitis C reflex testing to quantitative hepatitis C RNA assessment has increased diagnostic effectiveness and identified undiagnosed cases of hepatitis C.²⁷

ACTION ITEMS

Development of reliable diagnostic tests for anti-HDV and HDV RNA

• Reflex testing cannot be achieved without the availability of standardized, pangenotypic PCR assays. Moreover, the Achilles heel of efforts to eliminate hepatitis D is a lack of standardized testing. There can be no progress without adequate serological and virological tests.

Call for reflex testing for hepatitis delta among persons living with chronic hepatitis B:

• The Panel strongly urges CDC and the American Association for the Study of Liver Disease (AASLD) to recommend universal screening for hepatitis delta among people who are living with chronic hepatitis B, with reflex quantitative PCR testing for hepatitis delta RNA among those testing positive for hepatitis delta antibody.

PRIORITY FOCUS 4: FACILITATE RESEARCH ON LINKAGE TO CARE AND FOLLOW-UP

Once persons with hepatitis delta have been identified, clear guidance is lacking on what actions are needed for the reported cases in terms of linkage to care and follow-up. Some states provide guidance, but this is not consistently followed across jurisdictions. These factors complicate data collection by community groups, including assessment of the number of people in care services and research into how they are managing their treatment plans.

ACTION ITEM

Improve data sharing to facilitate research on linkage to care and follow-up:

• Assemble a network of hepatitis delta experts, and work with organizations such as the Hepatitis B Foundation and other nonprofits to develop a repository of HIPAA-compliant data, including mostly hepatitis delta blood test results mainly for use in primary care settings. Strategies for data sharing would need to be implemented without adding extra burden to primary care providers, perhaps leveraging the use of electronic health systems, where data are already collected. This type of study would need additional funding.

PRIORITY FOCUS 5: IMPROVE COMMUNICATION AND OUTREACH

Communicating with the public about hepatitis delta is challenging because health care providers and community organizations need to address cultural, language, and logistical barriers for the communities they serve. Many of these communities are marginalized, including those representing foreign-born and LGBTQ+ individuals. Because each of these communities has its own challenges and culture, communications strategies need to be tailored for each specific group. In addition, distrust of the medical establishment and perceptions of serving as “guinea pigs” prevent persons with hepatitis delta from enrolling in clinical trials. These factors, along with the stigma and fear associated with a hepatitis B or delta diagnosis, often hamper communications between persons living with hepatitis delta and their providers, and negatively impact outreach efforts by community-based organizations. Among high-risk populations, many people are reluctant to undergo testing specifically for viral hepatitis or HIV due to their association with sexual transmission and injection drug use. The communication around testing, therefore, has to involve a more holistic approach, in which the overall health of individuals is considered, rather than only stigmatized conditions. A focus on liver cancer prevention rather than routes of transmission of viral hepatitis should be included in effective communications. Simple and clear messaging is needed to dispel misconceptions about the different hepatitis viruses. Communication among providers is also important: providers should share testing information to raise awareness among their peers and optimize the coordination of care.

Given that individuals seek help within their communities, the outreach response to hepatitis B and delta must be community-based. Because of limited funding for public outreach in viral hepatitis, communications have mainly focused on hepatitis C, with much more small-scale efforts focused on hepatitis B. Public awareness of hepatitis B is, therefore, limited, and adding information on hepatitis delta can further complicate messaging. Communicating with legislators, an important aspect of raising awareness around hepatitis delta, also requires simple shared messages for hepatitis B, hepatitis delta, and liver cancer. The key information to be conveyed includes the number of people affected by each condition and overall outcomes in terms of the burden of cirrhosis and liver cancer. With the updated CDC recommendations for universal hepatitis B vaccination of adults aged 19–59 and universal hepatitis B screening for all adults, and the potential availability of effective new treatments for hepatitis delta, communications should be updated to highlight how these developments can make a major impact on reducing disease burden and improving care for people living with hepatitis B or delta.

ACTION ITEMS

Create simple messaging on the importance of screening and timely linkage to care:

• Incorporate hepatitis delta into all communications around newly updated universal adult hepatitis B vaccine and screening guidelines.

Build collaborations between national and community-based organizations to improve outreach:

• Ensure outreach reaches highly impacted communities, such as LGBTQ+ groups.
• Create and foster hepatitis delta-specific support groups.

CONCLUSION

Hepatitis delta is the most aggressive form of viral hepatitis, associated with more rapid progression to cirrhosis and an increased risk of liver cancer and death compared with hepatitis B monoinfection. Despite this, hepatitis delta remains largely unknown to the public, health care providers, community groups, and policymakers. A Roundtable Panel comprising various members of the viral hepatitis community identified several major challenges around the hepatitis delta, including a lack of awareness of the virus among the public and health care providers; complex risk-based testing protocols; a lack of accurate prevalence data; limited data on linkage to care; and inadequate communications among various stakeholders. The Panel suggested several strategies to address these challenges, such as improving and expanding education for different audiences, calling for simplified protocols for universal screening with reflex testing, expanding surveillance for hepatitis delta, requiring automated reporting and national notification, improving data sharing for research, and enhancing communications among different stakeholders. The recent CDC recommendations for universal vaccination against hepatitis B and universal adult hepatitis B screening, and the anticipated availability of new therapies for hepatitis delta present a unique opportunity to focus attention on HDV. The Roundtable Panel urges prompt action to make significant progress in addressing hepatitis delta among individuals living with hepatitis B.