Evidence-Based Strategies for Micro-elimination of Chronic Hepatitis B Virus Infection

Hepatitis B (HBV) remains a health threat around the world. Hepatitis C is closer to meeting the World Health Organization’s 2030 elimination goal compared to HBV. To achieve a successful micro-elimination and macro-elimination, there are certain objectives that need to be met. HBV infects more than 262 million people worldwide and is associated with significant morbidity and increased mortality. There have been previous HBV and hepatitis C virus micro-elimination trials with varying success. Micro-elimination programs should be designed to move services forward with a plethora of avenues for monitoring, testing, and treatment. Ultimately, successful and maintained micro-elimination is needed to achieve macro-elimination of HBV. Here, we propose 5 core tenets of micro-elimination that can be expanded to macro-elimination; these 5-line guidelines provide for 5 pillars of HBV management that support a path to a successful global elimination of HBV.


Introduction
Hepatitis B (HBV) is a viral infection that is a major cause of acute and chronic liver disease. HBV is cleared spontaneously in more than 95% of adults who have acute infection [1]. But HBV can also progress to a chronic disease state, which affects 262 million people worldwide. In the USA, there are around 2.4 million people who are infected with chronic HBV, with 60,000 new cases annually [1,2]. The Indian sub-continent, sub-Saharan Africa, and Central Asia are most affected due to limited access to health care.
In 2016, the World Health Organization (WHO) called for the elimination of HBV and hepatitis C (HCV) as public health problems by 2030, as defined by a 90% reduction in incidence and a 65% decrease in mortality compared to 2015 levels [3]. Unfortunately, as of March 2023, no countries are on track to achieve WHO elimination targets for HBV by 2030, which is in stark contrast to HCV, for which 9 countries are on track to achieve WHO elimination targets [4]. To combat this infection, we will review HBV microelimination goals and propose 5 pillars and a 5-line guideline to reduce HBV disease worldwide.

Micro-elimination
HBV carries some innate qualities making it more difficult to eliminate, such as the absence of a "true" cure for the disease, as well as the disease having the greatest mortality and morbidity in low-and middle-income countries where resources are limited [5]. However, inefficiencies in current approaches to eliminating HBV have also been documented. Several countries have enacted macro-elimination approaches to prevent and treat HBV, some even prior to the WHO announcement in 2016 [6][7][8][9][10][11][12][13]. Although of acute symptomatic HBV and hepatocellular carcinoma (HCC) in children [18]. This project encapsulated important elements of micro-elimination, including a specific focus group of need, a clearly outlined plan, collaboration between multiple stakeholders, and adequate follow-up demonstrating efficacy.
Here, we propose 5 core tenets for micro-elimination in HBV: 1. Following a 5-line guideline (Table 1) to identify those who are eligible for vaccination or treatment for chronic HBV infection 2. Identifying a specific focus group with limited access to care and/or decreased awareness of HBV prevalence in their community. 3. Preparing a dedicated plan tailored to the focus group that addresses 5 pillars of elimination: vaccination, stigma and awareness, screening and diagnosis, treatment, and forward-looking considerations. 4. Ensuring close collaboration of multiple stakeholders (government officials, health care providers, and individuals within the community including civil service organizations). 5. Providing adequate patient follow-up to monitor for efficacy, areas of improvement, and complications.

Five-Line Guideline for HBV in Adults
A recent Morbidity and Mortality Weekly Report (MMWR) advised testing all adults who are 18 years or older with a triple panel (HBsAg, anti-HBc, and anti-HBs) at least once in their lifetime [19••]. A study by the Infectious Disease Society of America found that screening all with HBsAg at least once is more cost-saving compared to the current American Association for the Study of Liver Diseases (AASLD) treatment recommendation alone [20 •]. This would prevent an additional 23,000 deaths from liver disease and liver cancer with an estimated savings of $596,000,000 [20•]. Therefore, universal screening of adults is cost-effective, while reducing transmission risk and identifying those at risk of HBV reactivation and those who will benefit from treatment or HBV vaccination [19••]. The current HBV treatment guidelines by EASL, AASLD, and the Asian Pacific Association for the Study of the Liver (APASL) are complex and impractical to implement [21,22]. Simplified treatment guidelines are needed. A start would be a simplified treatment plan by Dieterich et al., which recommended treatment for those without cirrhosis with HBV-DNA ≥ 2000 IU/mL who are 30 years or older or younger than 30 years with alanine transaminase (ALT) greater than the upper limit of normal [22]. However, we need a more simplified approach (Table 1). A recent study in North America found that lower percentages of African American (AA) or Blacks met the AASLD treatment criteria when compared to Asians and Caucasians [23•]. Therefore, the treatment initiation rates were higher among Asians and Caucasians compared to AA or Blacks [23 •]. It seems that Africa-born AA or Black participants had lower prevalence of HBeAg and genotype A2, compared to US-born participants [23•], which may be why they did not meet the treatment criteria [23•].
A study from China investigated the effect of expanding chronic HBV therapy to those with elevated ALT levels versus HBsAg-positive individuals [24••]. The study found that treating HBsAg-positive, regardless of ALT levels, with 80% coverage allowed them to achieve WHO's 2030 goal [24••]. This approach had the highest reduction in HBVrelated complications and the highest quality-adjusted lifeyears compared to ALT level-based treatments [24••]. Additionally, this approach was more cost-effective in the long run by 2025 [24••].
There is a risk for HBV spread even with the clearance of HBsAg, because there can still exist low levels of HBV-DNA in the bloodstream in a subset of patients [25]. Patients with occult hepatitis B infection (OBI) still have a risk of HBV spread [26,27] and have a reactivation risk during chemotherapy, HCV therapy, or immunosuppressive therapy [28]. A recent study found that the baseline HBV-DNA plus HBV RNA was more positively correlated with cccDNA than quantitative HBsAg. This is because HBsAg is also produced by HBV-DNA integrated into the host genome [29]. Importantly, the persistence and disease sequalae of chronic HBV infection are due to cccDNA [30]. For example, there is still a risk for HCC and cirrhosis development in patients with detectible HBV-DNA or intrahepatic cccDNA [31].
The current treatment recommendations are complicated; for example, AASLD, EASL, and APASL all have different criteria to stop therapy in CHB [37][38][39]. Nevertheless, all societies agree that patients with CHB and those with compensated cirrhosis can discontinue antiviral therapy if HBsAg loss persists for at least 1 year [36][37][38][39]. We recommend treating everyone who is HBV-DNA-positive, until they are HBsAg-negative and HBV-DNA-negative for at least 12 months (Table 1).

Five Pillars for HBV Elimination
1st Pillar: HBV Screening, Diagnosis, Virology, and Surveillance Previously, recommendations of risk-based testing for HBV have failed, as it did for HCV and HIV. To eliminate HBV, the Centers for Disease Control and Prevention (CDC) updated their recommendations for the first time since 2008 to expand testing for all adults with a triple panel of HBsAg, anti-HBs, and total anti-HBc least once in their lifetime [19••]. Expanding screening was partly influenced by findings that 67% of HBV carriers were unaware of their infection and the cost-effectiveness of universal screening [19••]. The US Department of Health and Human Services found that from 2013 to 2016, only 32% of chronic HBV carriers were aware of their infection contributing to the underdiagnosis of cirrhosis and HCC [40]. Increased screening efforts for HCV across communities in the USA, including the Northshore University Health System, resulted in successfully screening 64.3% of the eligible population born between 1945 and 1965 [41].
Acute HBV infection, similar to chronic HBV infection, has the diagnostic presence of hepatitis B surface antigen (HBsAg) [42]. In chronic HBV, viral replication will persist throughout the rest of their life resulting in a persistently positive HBsAg [42]. A key component to differentiate the 2 is that only in acute HBV will there be a presence of IgM hepatitis core antibody (anti-HBc) [42]. In some instances, where HBsAg is rapidly cleared by the body, only IgM anti-HBc will be positive in acute HBV infection [42]. The presence of anti-HBs alone remains the standard to detect immunity against the virus. OBI is a condition where viral DNA is present in the liver [43]. Most patients are found to have HBV-DNA levels around 20,000 to 90,000 copies/ mL, but much lower titers of HBV-DNA levels can also be observed [44][45][46]. In this state of chronic HBV, the covalently closed circular DNA (cccDNA) is replicating at a lower rate; thus, the HBV-DNA presence for diagnosis is inconsistent on serum serologies. Other serology markers for OBI are shown in Table 2 [43].
Current HBV golden standard testing is carried out by enzyme immunoassay (EIA) with an analytical sensitivity of 0.05 IU/mL for most commercial tests [48]. Rapid diagnostic tests (RDT), also known as point-of-care tests, are widely being studied to make HBV testing more available. They minimize turnaround time, require less blood, are easier to interpret, and can detect HBV sooner [49]. Determine™ HBsAg 2 is the most popular RDT and has shown a sensitivity of 90.8% and specificity of 99.1%; however it drops to 56-100% sensitivity in populations infected with HIV [50]. Though RDTs are less accurate than current gold standard testing, they present a promising alternative for low-resource settings burdened with underdiagnosis of HBV. Like the success of Egypt, who is achieving WHO's targets, countries need to consider rolling out free RDTs due to their ease of interpretation and availability to increase access to testing [51]. Increased accessibility to testing is imperative to achieve micro-elimination of HBV.
The AASLD 2018 guidelines recommends chronic HBV carriers without cirrhosis to have surveillance for HCC with an ultrasound +/− alpha-fetoprotein (AFP) every 6 months [52]. Sadly, less than 40% of patients undergo annual HCC surveillance [53]. Improved HBV surveillance is a key component in preventing progression of disease and mortality. As new policies and guidelines are unveiled, consistent surveillance is an important tool to monitor micro-elimination efforts in the context of incidence, progress, and mortality benefit [51].

2nd Pillar: Vaccination
Because there is no true cure for HBV, prevention of the disease by vaccination is a core component for micro-elimination. Currently, the WHO recommends HBV vaccination in all children worldwide, including a monovalent "birth dose" vaccine within 24 h of birth, as well as vaccination of high-risk groups [54]. Additionally, WHO guidelines recommend that infants of HBsAg-positive mothers should receive both the hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) within 12 h after birth, followed by the next 2 doses of the vaccine at 1 and 6 months old.
As of May 2022, over 80 countries were on track to achieve a target HBsAg prevalence of ≤ 0.1% in children ≤ 5 years old [55]. However, while promising, this progress must be taken with a grain of salt, as socioeconomic factors severely skew the data. Although most high-income countries such as the USA have already achieved a HBsAg prevalence of ≤ 0.1% in children ≤ 5 years, lower-income countries still carry a prevalence of up to 8.0% [56]. Unfortunately, many lower-income countries are unable to incorporate a birth dose vaccine or HBIG into their universal vaccination protocols due to cost and logistics, thus having inadequate coverage for their vaccination programs [57]. For reference, even though the majority of member WHO countries have implemented universal childhood vaccination programs, just over half adopted a policy to provide a birth dose vaccine [58]. For many resource-limited countries, pentavalent or even hexavalent vaccines are supplied free of charge by GAVI (the Vaccine Alliance). These combination vaccines cover additional diseases but can only be administered 6 weeks after birth and do not include a birth dose vaccine (Table 3).
Fortunately, regions lacking the birth dose vaccine represent a critical focus group that can be targeted by microelimination studies. A micro-elimination effort in the capital of Vietnam demonstrated a gap in existing vaccination programs [59]. Pham et al noted that Vietnam had implemented a universal childhood vaccination program since 2003 but found in their study that less than < 20% of the adult population was vaccinated despite 37.7% of adults being susceptible to HBV infection. As such, vaccinating triple-negative patients who are susceptible to HBV infection is an important consideration for future micro-elimination projects. The importance of screening triple-negative patients was highlighted when the USA recently revised their guidelines to recommend screening all adults ≥ 18 years old with HBsAg, Table 2 HBV serology markers [47] Abbreviations anti-HBs, and anti-HBc [19]. Recently, a novel 2-dose vaccine (Heplisav-B) with doses spread apart by only 1 month was introduced to facilitate efforts to "catch up" susceptible adults who are triple-negative. Beyond the improved convenience of less doses, Heplisav-B is also notable for superior efficacy compared to traditional 3-dose vaccines (Table 3) [60]. In summary, vaccination as a prevention for HBV is a powerful tool for a disease that otherwise lacks truly curative therapies. When possible, we recommend that all microelimination efforts should emphasize not only universal childhood vaccination but ensure also the coverage of a monovalent birth dose vaccine as well as HBIG. Additionally, all adults should be screened with HBsAg, anti-HBs, and anti-HBc, and triple-negative patients should be linked with appropriate care. The HBV vaccine is safe and effective, and vaccinating all susceptible individuals can reduce overall transmission.

3rd Pillar: Reducing Stigma and Improving Quality of Life
Stigma is the social process by which perception results in unwarranted adverse judgment about a person or group through the means of exclusion and/or rejection [61]. There are 3 categories of stigma: social, internalized, and institutional [62]. Social stigma of HBV is largely due to the assumption that those who live with the disease endorse a risky lifestyle that involves illicit injection drug use or unprotected sex [63]. The implications are vast and can result in delays in seeking care for those suspected of being at risk of having the virus. From the perspective of microelimination of the virus at the global level, this substantiates the problem due to many unaware people living with the disease who are potentially transmitting the virus onward [62].
Smith-Palmer et al. published a robust systematic literature review in 2020 on stigma in patients with chronic HBV using a total of 23 articles, 17 of which were quantitative and 6 qualitative [62]. Stigma was best characterized in China whereas studies in the North America, Europe, and Africa were lacking, which is in line with China having the highest prevalence of HBV in the world. They found that in China, a large proportion of stigma was attributed to fear. This was perpetuated by a law (i.e., institutional stigma) that allowed employers and colleges to screen applicants for HBV and deny them based on their result. The antidiscrimination law was not banned until 2010; however, that has not prohibited employers from working around the law to ask their applicants to take a voluntary test [62]. Institutional stigma resulted in Smith-Palmer et al.'s finding that up to 20% of chronic HBV carriers believed they would be denied health care [62]. This highlights the importance of efforts to reduce stigma in the context of micro-elimination.
Stigma contributes to lower health-related quality of life (HRQoL) and mental health in chronic HBV carriers [63]. Patients who are newly diagnosed with HBV should undergo training in coping strategies. Therapy and on-line support groups are methods that provide a platform to share their experiences and create a supportive network [64]. Similarly, Li et al.'s study also found that HBV-related stigma adversely affected HRQoL in many facets of life, especially in the early stages of the disease where fear of acceptance was the greatest [65]. This emphasizes the importance of providing education, therapy, and support for patients at the time of diagnosis. Additionally, stigma can also lead to disengagement and decreased treatment compliance thereby leading to increased mortality [64]. Similar to how efforts have been made through posters and television to reduce stigma associated with HIV, effective ways of spreading awareness and educating the public on HBV should also be undertaken [66]. Raising awareness is an important aspect of stigma and micro-elimination projects. Two separate community-based outreach programs in the USA demonstrated how establishing strong ties within a community contributed to increased success of HBV screening, diagnosis, and surveillance [67,68]. It is imperative to implement public health strategies that are aimed at reducing the burden of stigma to meet goals for micro-elimination of HBV.

4th Pillar: Reducing Infectivity with Enhanced Treatment Recommendations
Surprisingly, about two-thirds of those with chronic HBV are not aware of their infection [69], and unfortunately, HBV is 50-100 times more infectious than HIV [70]. HBV can survive outside the body for at least 7 days, and during this time, it can still cause infection [71]. In addition, those with HBV-DNA positivity are more infectious than those who are HBV-DNA-negative due to the high viral load. HBV is so infectious that 9% of newborns born to a mother with chronic HBV infection, who received appropriate passiveactive immunoprophylaxis, will still acquire HBV infection [72]. This risk is truer for those who are born to mothers with a viral load higher than 8 log 10 copies/mL (7.3 log 10 IU/ mL) [73]. Sadly, newborns have a 90% chance of developing a chronic infection after being infected with HBV [72].
Unfortunately, at-risk mothers in resource-limited settings may be unable to access adequate health care facilities. Indeed, the prevalence of home births is higher in these settings due to both socioeconomic and cultural factors, and these mothers and their newborns often lack access to immunoglobulin treatment or vaccinations at home and have delays to access a proper health care facility with vaccine capabilities [57]. Prophylactic treatment of pregnant mothers with antiviral treatment during gestation has previously been proposed as an alternative solution in eliminating mother-to-child-transmission in underserved populations [74]. In remote regions along the border of Thailand and Myanmar, Bierhoff et al. demonstrated promise in prophylactic daily antiviral therapy started early in gestation as a substitute for mothers who are unable to access immunoglobulin or vaccines with a facility birth [75]. This indication for prophylactic tenofovir use was also used in Thompson et al [76].
The risk of HBV infection after blood exposure can still occur with low levels of HBV-DNA. There have been reported infections with viral copies as low as 2-5 copies/ mL. However, no infection has been reported for HBV-DNA level around 200 copies/mL [77]. Some have suggested that a minimum infection dose may be as low as 16 copies/mL [78]. This further solidifies the need to treat everyone who is HBV-DNA-positive.
Previous treatment recommendations are complicated and is based on ALT and HBV-DNA levels [79]. These complicated guidelines have resulted in less than 20% of chronic HBV infections being treated [71]. Here, we recommend treating all who are HBV-DNA-positive (Table 1). This is because there is a very small difference between those who are HBV-DNA-positive and HBsAg-positive. Although, the HBsAg seroclearance is rare with current treatments (1-10%) [80], it will reduce the infectivity of those with chronic HBV infection. By screening all adults for HBV and treating all who are HBV-DNA positive, we are more likely to identify and treat those who are infectious. Reducing the infectivity of those with chronic HBV and thus reducing the risk of HBV spread are an important step towards HBV elimination.
There are different definitions of HBV "cure": complete and sterilizing cure, functional cure, and partial cure (Table 5) [84]. The current goal is to achieve functional cure as it is associated with better clinical outcomes, and it is more feasible with current available treatment. Unfortunately, there is only about 1-10% chance of HBsAg seroclearance (HBsAg loss) [80] and functional cure is extremely rare (< 1% of patients per year) [79,85] with the current therapies. However, even with low rates of functional cure, there still is a clinical benefit of antiviral therapy and lowering HBsAg and HBV-DNA levels. The clinical benefits are reducing risk for liver cirrhosis, HCC, extrahepatic manifestations, liver transplant, and mortality [80,86,87] and improving QoL [88]. Therefore, we recommend treating all who are HBV-DNA-positive until HBsAg loss in efforts towards HBV elimination and improved QoL.

Future for HBV Elimination
To eliminate HBV, there needs to be improved access to care and uptake of HBV therapy regionally and nationally around the world. There are many challenges to accessing clinical services and obtaining treatment in both the developed and developing world [4]. The shortage of liver specialists in low-and middle-income countries and the placement of specialists at tertiary centers in high-income countries limit access to patients [89]. There are not enough hepatologists and infectious disease physicians to treat all with HBV. To combat this, local primary care physicians, nurse practitioners, pharmacists, and physician assistants should be trained to treat HBV. Previously, training local medical practitioners has shown to improve HIV and HCV diagnosis and treatment [90,91], and this should extend to HBV as well. A recent study predicted the effects of improved antiviral treatment coverage for the population with higher incidence of HBV infection [92]. Using a mathematical model, Taye et al. found that improved antiviral coverage of 20% resulted in reduced HBV-related mortality and chronic HBV cases. To improve our chances of HBV elimination, there needs to be improved access to care as well as an increase in the number of patients with chronic HBV receiving antiviral treatments.
The covalently closed circular DNA (cccDNA) serves as a stable reservoir for HBV infection. A major limitation in achieving complete or sterilizing cure is that current available therapies do not eradicate the cccDNA in hepatocytes and integrated HBV-DNA. There is a constant replenishment by incoming virions and recycling of cccDNA within the hepatocytes [84]. NAs and INFs block reverse transcription within the hepatocytes but have only a small effect on cccDNA production [84]. Additionally, current treatments have very little effect on the HBsAg production and do not modify the immune response [93,94]. This is the reason why present treatment is more of a suppressive therapy with the expectation of long-term treatment. Fortunately, there are many new therapies in the pipeline that can improve rates of functional cure, HBsAg loss, and HBV-DNA negativity ( Table 6). These new antivirals, immunomodulators, and vaccines target different aspects of the HBV life cycle. These can be found in PubMed and on the Drug Watch of the Hepatitis B Foundation website. With these new emerging therapies, we may be able to  Detectable HBsAg but persistently undetectable HBV-DNA effectively target multiple mechanisms for which cccDNA is recycled and replenished. Therefore, we may be able to achieve a finite course of HBV therapy and possible HBV cure using a multi-drug approach.

Conclusion
Currently, we are not projected to meet the WHO's goal to eliminate HBV as a health threat by 2030. To assist in achieving this goal, we propose guidelines for future elimination of HBV. To achieve macro-elimination, we first need to be successful at micro-elimination. We presented 5 core tenets of micro-elimination to help guide future elimination programs. Secondly, we brought forth A 5-line guideline to simplify the approach and treatment of HBV in adults. This will increase identification and treatment for those with chronic HBV while identifying those who are eligible for vaccine. Thirdly, we outlined 5 pillars of HBV to emphasize important aspects of HBV prevention, illness, and treatment. With these 5 core tenets of microelimination, the 5-line guideline, and 5 pillars of HBV, we hope for a successful and maintained micro-elimination and ultimately macro-elimination of HBV.
Author Contribution Robert Gish and Katerina Roma contributed to the design of the paper. The first draft of the manuscript was written by Katerina Roma, Mark Hsu, and Adam Khattak. All authors contributed to the revision of the article and approved the final manuscript.

Data Availability
The authors confirm that the data supporting the findings of this paper are available within the article.

Compliance with Ethical Standards
Conflict of Interest No potential competing interest was reported by the authors. There are no financial or non-financial interests that are directly or indirectly related to the work submitted for publication by all authors.

Human and Animal Rights and Informed Consent
The research does not involve human and or animal subjects.
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