Problems remaining to be solved
There remain a number of challenges in the diagnosis and management of patients with chronic hepatitis B infection - Figure 1.
Figure 1 Remaining challenges in hepatitis B virus infection.
HBV: Hepatitis B virus; cccDNA: Closed circular DNA; HCC: Hepatocellular carcinoma; pgRNA: Pregenomic RNA.
Diagnosing and linking infected patients to care programmes: A significant proportion of infected persons have not been identified; current estimates suggests that only 10.5% of infected individuals have been diagnosed and only 5% of those eligible for treatment for chronic HBV infection are receiving treatment. A large systemic review found that 10% of people (26 million) with HBV infection might need urgent treatment due to cirrhosis and 12%-25% of patients would also be eligible for treatment according to different international guidelines. Many countries do not have the infrastructure to deliver widespread testing, vaccination or treatment; this is particularly true in low-middle income countries where resources are limited. Detailed discussion on the challenges of such health inequalities are beyond the scope of this review. The approach to up-scaling diagnostic testing needs to vary according to the target population. In the United Kingdom and other developed countries, the majority of individuals with undiagnosed hepatitis B infection are born in countries with intermediate or high prevalence rates. Identifying these individuals may increase diagnosis rates. Case finding in high-risk groups is effective; in North-East England, individuals from the British-Chinese and South Asian communities were invited to education and screening (via dry blood spot testing) sessions in local community centres. The prevalence of hepatitis B surface antigen (HBsAg) positivity was 4.6%, which is above the 2% screening threshold recommended by the Centers for Disease Control and Prevention. Another study looked at the cost-effectiveness of a one-time opt out case-finding approach in a primary care setting in the United Kingdom migrant population. This approach was deemed very likely to be cost effective amongst migrant populations with HBsAg prevalence ≥ 1%.
New point of care (POC) tests are also becoming available, making diagnosing infection easier and quicker. For example, the Determine HBsAg 2 test provides a HBsAg result in 15 min with high sensitivity and specificity. POC tests allow testing and diagnosis to move out of established health care settings and may be of particular utility in resource poor settings and high-risk communities.
Increasing testing and subsequent diagnosis rates relies on public engagement to break down stereotypes and address stigma, improved interactions with health care services and addressing health inequalities arising from poverty and language barriers[34,35]. Collaboration and integration with other successful public health programs such as human immunodeficiency virus (HIV) services is also likely to be effective.
Defining cure: A ‘cure’ for HBV might be considered as one where the virus is completely eliminated [undetectable HBsAg, HBeAg, HBV DNA and hepatic covalently closed circular DNA (cccDNA)] and where any (risk of) associated liver disease is also removed. Consensus on definitions of cure remain contentious and as there is no current or upcoming treatment to achieve the ‘holy grail’ described above, there is reticence in how the word ‘cure’ is used. However, this is a key aspect of clinical care and research, therefore a globally accepted definition of cure needs to be obtained.
The term ‘sterilising cure’ (complete eradication of the virus) has been replaced with ’functional cure’. Functional cure is currently defined as sustained HBsAg loss, undetectable HBV DNA, with or without seroconversion to hepatitis B surface antibody, following a finite course of treatment and it occurs in 1% of chronically infected patients annually. However, HBV genomes can persist in the liver even if HBsAg is undetectable questioning the true value of achieving a functional cure. A ‘partial functional cure’ is considered an intermediate goal of therapy and signifies detectable HBsAg but persistent undetectable HBV DNA 6 mo post-treatment. Virologic cure is essentially ‘halting’ all forms of HBV replication, however difficulties with obtaining virologic cure remain due to the persistence of cccDNA in hepatocytes. To obtain virologic cure, treatments inhibiting both cccDNA and viral replication are required.
An agreed definition of cure remains elusive, however with clearly defining treatment endpoints and new therapies targeting different aspects of the HBV life cycle, virologic cure may be achievable in the future.
Striving for prevention rather than cure: To prevent HBV infection, there needs to be a focus on improving vaccination strategies. Barriers to HBV vaccination, particularly in resource limited or remote regions, can be attributed to inadequate resources to acquire vaccinations, current dosing regimens, insufficient trained health staff for administration of the vaccine and lack of facilities to keep vaccinations between 2-8 oC. One study of a two-dose regime of HBsAg-1018 (containing HBsAg plus a toll-like receptor 9 agonist adjuvant) demonstrated a higher seroprotection rate at one year compared with the standard three dose regimen. Simplified regimens with fewer doses over a shorter time period (HBsAg-1018 given at 0 and 4 wk) are likely to be associated with increased uptake. Many countries have now instituted effective COVID-19 vaccination programmes, and similar systems could be used to roll out simplified HBV vaccination regimens.
Preventing mother to child (vertical) transmission of hepatitis B is vital if global elimination is to be achieved[40,41]. High maternal viral load is the greatest risk factor for mother to child transmission; HBeAg positivity also increases risk. In resource poor settings the WHO-recommended vaccine strategy may be difficult to deliver, and diagnostic assays for HBV testing may not be readily available. A potential strategy in these settings is POC testing to establish HBeAg status, followed by empirical treatment with tenofovir in the 3rd trimester in those who are HBeAg positive to reduce viral load and the risk of perinatal transmission, however such diagnostic assays are not readily available and remain costly.
Defining ‘stopping rules’ for HBeAg negative patients treated with NAs: Where seroconversion of HBeAg occurs, 67%-85% of patients have a sustained inactive state (HBeAg negative chronic infection); this is particularly the case where seroconversion occurs below the age of 30 years and where a low or undetectable HBV DNA level has been maintained. However, given significant relapse rates it remains controversial as to whether NA treatment can be stopped after HBeAg loss. A HBeAg negative state is associated with higher rates of regression of fibrosis but some patients will develop HBeAg negative hepatitis, the risk of which increases with time (22% at 10 years) and increases the risk of progression to advanced liver disease.
Given the low rate of clearance of HBsAg, HBeAg seroconversion is considered as a potential endpoint of treatment, where undetectable HBV DNA is achieved on three separate occasions in a 6 or 12-mo period. If treatment is stopped at this endpoint, 50% will undergo HBeAg reversion requiring treatment with NAs to restart; close biochemical monitoring is therefore required. There is evidence to suggest that longer treatment with NAs results in a higher chance of persistent remission, with viral remission for 24-mo on NAs offering the most likely chance of sustained remission.
Therefore, currently there is no universal stopping rule. In real-world practice, many different factors are taken in to consideration when making the decision to stop treatment with NAs, including the stage of fibrosis and family history of hepatocellular carcinoma (HCC). Further studies are needed to more clearly define the predictors of sustained remission and/or relapse to guide stopping decisions.
Establishing treatment endpoints - aiming for viral suppression vs cure: Currently, long-term suppression of HBV DNA levels is the main endpoint of treatment (+/- HBeAg loss in HBeAg positive patients). It remains a subject of debate as to whether the endpoint of treatment should be viral suppression, functional cure, partial functional cure or virologic cure. The ideal goal however would be virologic cure. In 2019 the joint EASL-American Association for the Study of Liver Diseases HBV treatment endpoints conference agreed that a “functional cure” should be the primary endpoint of phase III trials; sustained HBsAg loss in more than 30% of patients was accepted as an acceptable rate of response in phase III trials. The endpoint for trials may not be the same as the endpoint for real world clinical practice however.
Biomarkers continue to be developed and may prove useful in defining future treatment endpoints. These biomarkers are likely to be used in conjunction with currently utilised clinical markers. The development of hepatitis B core-related antigen (HBcrAg) as a potential serological marker for cccDNA levels may identify patients who could discontinue NA therapy, those at risk of HCC development or of recurrence following treatment[28,46]. Pregenomic RNA may be a novel marker of viral replication; evidence is emerging that this may provide an earlier predictor for HBeAg seroconversion for those patients on NAs (an important indicator for partial immune response) and may help guide future treatment in those not achieving HBeAg seroconversion.
Establishing a universally accepted endpoint of treatment along with biomarkers to help predict or confirm the achievement of this endpoint would be an important advance in the treatment of chronic HBV infection.
Risk of HCC and surveillance in patients on long term NAs: Chronic HBV infection is a leading cause of HCC; it is responsible for around 25% of liver cancer cases in developed countries and up to 60% of cases in developing countries. NA therapy has been reported to decrease incidence of HCC[49,50]. While HBsAg loss after the development of advanced fibrosis minimizes the risk of the development of HCC, it does not negate it completely. A number of factors are taken into consideration when deciding which patient to survey for HCC including disease phase, age, ethnicity and family history of HCC; international guidelines do not agree on the populations for surveillance however, promoting inequalities in care.
In those on NA therapy, risk scores such as the REACH-B score or PAGE-B score are used to identify patients who would benefit from HCC surveillance. The REACH-B scoring system was developed in a cohort of Asian patients with chronic HBV infection who were treatment naïve; no patients with cirrhosis were included in the development of this score. This score does not offer good predictability in Caucasian patients with chronic HBV infection. The modified REACH-B score substituted HBV DNA levels for the liver stiffness value which increased its accuracy. The PAGE-B score was developed for use in Caucasian populations receiving tenofovir or ETV. A modified PAGE-B score (addition of serum albumin) has recently been tested in Asian patients on NA therapy, with an area under the receiver operating characteristic curve of 0.82. The PAGE-B score is also predictive of HCC development in untreated patients.
Quantitative HBsAg and HBcrAg have been proposed as new biomarkers for HCC risk which might influence patient selection for HCC surveillance. Risk models incorporating these biomarkers would be an advance in the field of HBV. New models could also incorporate other novel markers such as specific HBV mutations, presence of the metabolic syndrome and HBV genotype.
Identifying new treatments with finite duration and high cure rates: Most patients with chronic HBV currently require lifelong therapy, achieving viral suppression rather than cure[25,26]. To achieve cure, combinations of therapy targeting different aspects of the HBV lifecycle are likely to be required including inhibition of cccDNA and viral replication.
A number of new treatments are being investigated for HBV and these are aiming to achieve clearance of HBsAg rather than just suppressing HBV DNA. A detailed description of these treatments is beyond the scope of this review, but these include the development of new NAs (besifovir and metacavir), cccDNA silencers (e.g., lymphotoxin beta receptor agonist) and HBV entry inhibitors (Myrcludex B)[28,38,56]. There may also be a role for immunomodulatory therapies such as toll-like receptor agonists (acting via activating the innate immune response), check point inhibitors (helping to restore T-cell dysfunction) or therapeutic vaccines such as TherVacB[56,57]. Gene editing strategies and RNA interference may be other potential treatment strategies. Where eligible, patients should be considered for entry into clinical trials of novel therapies.
Problems remaining to be solved
Identification of infected patients: A positive HDV antibody should be accompanied by detectable serum HDV RNA to detect active infection. However, some guidelines do not explicitly make recommendations for HDV testing and therefore many patients who are HBsAg positive are not tested for HDV. One study looking at clinic-led anti-HDV testing identified that only 40% of HBV patients were tested. The same study looked at a different centre offering reflex laboratory testing and found that 99.4% of first HBsAg positive samples were tested for anti-HDV. This is a potentially reliable approach to increasing detection of patients with HDV infection, as all patients who are newly diagnosed with HBsAg positivity should be tested for serological evidence of HDV infection.
There is an epidemiological association between anti-HDV seroprevalence and PWIDs, commercial sex workers, MSM and recipients of haemodialysis[58,62]. Suggested patient groups who should be prioritised for screening for HDV include: Patients who are HBsAg positive, patients with HIV, PWIDs, MSM and migrants from highly endemic regions.
Treatment for HDV infection: Pegylated-interferon (PEG-IFN) is the only treatment proven to have antiviral efficacy against chronic HDV infection, however viral suppression rates with PEG-IFN are poor in HDV infection and the adverse effects of PEG-IFN therapy are well described[62,63]. Extended duration of treatment has not been associated with a consistent or significant increase in efficacy, and the addition of NAs does not improve efficacy. New treatments are urgently required; therapies currently being evaluated include HBV/HDV entry inhibitors (Myrcludex B), virion secretion inhibitors (REP 2139) and inhibitors of the prenylation of the large HDV antigen (lonafarnib). Patients with HBV/HDV co-infection should be considered for entry into clinical trials. Ultimately, global prevention of HBV infection would be the most effective means of treating HDV infection.
Establishing treatment endpoints: Unfortunately, endpoints for HDV treatment and indicators of response to treatment have not been well established. Cure may not be feasible. ALT normalization, changes in HDV RNA and qHBsAg are markers of response to treatment. Barriers to establishing treatment endpoints include lack of widespread availability of HDV diagnostics and lack of standardization of HDV RNA assays. Composite endpoints are likely to be more useful than singular end-points.