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KGHeBTA (King George's Medical University Hepatitis B Therapeutic Algorithm): A New Diagnostic and Therapeutic Algorithm and Clinico-epidemiological Spectrum of Hepatitis B
Diagnostic and therapeutic algorithms given by various societies for hepatitis B are fragmented and complex. The clinico-epidemiologic spectrum of hepatitis B is not studied with large-scale data from our region. We aimed to develop a comprehensive algorithm for the treatment of hepatitis B and study its clinico-epidemiological spectrum.
Methods
From 2014–2019, the clinico-laboratory data of hepatitis B surface antigen (HbsAg)-positive patients were prospectively recorded. King George's Medical University hepatitis B therapeutic algorithm (KGHeBTA) was developed on the basis of the standard existing guidelines. The prevalence of different clinical stages of HBsAg-positive patients was calculated and their treatment records reviewed. Testing circumstances and risk factors were noted.
Results
Among 1,508 data record sheets, 421 were complete. According to the KGHeBTA algorithm, 221 had detectable hepatitis B virus DNA. 21% were cirrhotic and 79% non-cirrhotic. 72% were incidentally detected asymptomatic hepatitis B, 7% were hepatitis B with acute symptoms, 0.7% were acute hepatitis B, and 22% were chronic hepatitis B. 20% patients were eligible for antivirals and 80% patients were not eligible. 32% patients were actually treated with antivirals due to the inclusion of some special indications as pregnancy and family history. Screening during various medical illnesses (40%) was the most common and during health camps (0.2%), the least common testing approach. Road-side shaving (52%) was the most common and intravenous drug abuse (0.2%) and the least common risk factor for the detection of hepatitis B in our data pool.
Conclusions
HBsAg-positive patients can be easily worked up and treated based on the proposed algorithm (KGHeBTA). About one fourth to one fifth of all HBsAg-positive patients were eligible and treated with oral antivirals. Most of the patients were incidentally detected asymptomatic hepatitis B screened powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation during medical illnesses. Roadside shaving and intravenous drug abuse were the most and the least common risk factors.
Hepatitis B virus (HBV) is a leading cause of chronic liver disease and its related complications worldwide. Hepatitis B prevalence is highest in the Western Pacific Region (6.2%) and the African region (6.1%). Estimated prevalence of HBV in the Eastern Mediterranean region is 3.3%, in the South-East Asia region is 2.0%, in the European region is 1.6%, and in the region of the Americas is 0.7%.
But there is a scarcity of data for the prevalence of various clinical phases of hepatitis B. And thus, the data on the proportion of HBsAg (hepatitis B surface antigen)-positive patients, eligible for treatment by any therapeutic agent, are also lacking, which are important for policy making for large scale population based-treatment programs.
It is not always easy for a clinician to decide whether to start antiviral for an HBsAg-positive patient or just to monitor. The World Health Organisation (WHO) has given simplified treatment protocols based on the presence or absence of cirrhosis and alanine transaminase (ALT) plus HBV-deoxyribonucleic acid (DNA) levels, regardless of the HBeAg status.
still HBsAg is mostly screened in high risk or special circumstances only. There are limited data on the relative contribution of these screening circumstances (testing approaches) for the detection of HBsAg. In moderate to high prevalence areas, HBV is transmitted mostly vertically but horizontal modes of transmission are also described.
There are scarcity of large-scale data from our region for the possible risk factors for the horizontal transmission of hepatitis B.
Our study was primarily aimed to develop a comprehensive, diagnostic and therapeutic algorithm, King George's Medical University hepatitis B therapeutic algorithm (KGHeBTA), for day-to-day practice, based on the current guidelines. The secondary objectives were to calculate the prevalence of the various phases of hepatitis B and to calculate the proportion of patients eligible and not eligible for oral antivirals. The frequency of common circumstances for the detection of HBsAg and common risk factors for the transmission of hepatitis B were also calculated.
Material and methods
Study Design, Setting and Population
A comprehensive diagnostic and therapeutic algorithm (Figure 1) was developed based on various existing guidelines.
A retrospective analysis of the data collected on a predesigned proforma was done. Data were anonymised before analysis. The study was carried out at the hepatobiliary clinic of the Department of Medicine of our institute, between 2014 and 2019. All HBsAg-positive patients were included in the study. HBsAg was repeated by an enzyme-linked immunosorbent assay from our institute, and if it came negative, they were considered false positives and excluded. Those patients already on treatment with any antiviral or with incomplete records were excluded from the final data analysis.
Figure 1KGHeBTA: King George's Medical University hepatitis B therapeutic algorithm (#Clinical criteria: Decompensated cirrhosis is defined by the development of portal hypertension (ascites, variceal haemorrhage and hepatic encephalopathy), coagulopathy or jaundice. Other clinical features of advanced liver disease/cirrhosis may include: hepatomegaly, splenomegaly, pruritus, fatigue, arthralgia, palmar erythema and oedema. ∗ Rule out other causes of acute hepatitis: Hepatitis A virus, Hepatitis E virus, autoimmune, acute Wilson's disease, toxic and drug induced hepatitis, sepsis, others.).
First step for any HBsAg-positive patient was whether HBV-DNA was detectable or not, and the second was the presence or absence of cirrhosis. Cirrhosis was defined on the basis of clinical, biochemical, imaging and endoscopic findings.
Non-cirrhotic HBsAg-positive patients, having jaundice and other prodromal symptoms, were defined as hepatitis B with acute symptoms (HBWAS). HBsAg detected incidentally during screening in non-cirrhotic patients was defined as incidentally detected asymptomatic hepatitis B (IDAHB). Both HBWAS and IDAHB were followed, and if HBsAg became negative within 6 months of detection, they were defined as acute hepatitis B (AHB). The persistence of HBsAg for more than six months and the absence of the features of cirrhosis were defined as chronic hepatitis B (CHB) without cirrhosis.
The CHB without cirrhosis was categorised into five phases on the basis of standard guidelines: HBeAg-positive chronic HBV infection (immune tolerant), HBeAg-positive chronic HBV hepatitis (immune clearance), HBeAg-negative chronic HBV infection (inactive), HBeAg-negative chronic HBV hepatitis (reactivation) and HBsAg-negative phase (resolved HBV infection), taking into account the presence of HBeAg and HBV DNA levels, ALT values and last HBsAg report.
An indeterminate class was defined when patients did not fit into any of these classes (Figure 1).
The presence of intrahepatic space-occupying lesions detected by at least two imaging modalities after applying the CT/MRI LI-RADS® diagnostic algorithm was defined as the presence of hepatocellular carcinoma (HCC).
Criteria for eligibility to start antiviral were: I) all cirrhotics with any level of detectable HBV DNA; II) those in the chronic hepatitis phase [i.e. ALT more than two times and a) HBeAg positive with HBV DNA >2 × 104 IU/ml (immune active phase) and b) HBeAg negative with HBV DNA >2 × 103 IU/ml (reactivation phase)]; and III) those with age equal to or more than 30 years in a) HBeAg-positive chronic infection (immune tolerant phase) and b) indeterminate class (Figure 1).
Those in the AHB, IDAHB, chronic infection phase (the inactive phase and immune tolerant/indeterminate classes except those with age more than 30 years) and resolved HBV infection were considered not eligible for oral antivirals (Figure 1). The special indications for treatment with antivirals were pregnancy [for prevention of mother to child transmission] and a strong family history of hepatitis B-related morbidity. HBsAg, HBeAg, HBV-DNA and liver function biochemistries were repeated every 3–6 months on follow up.
Data Collection
Demographic, clinical (including the details of history and examination with a special emphasis on risk factors, testing circumstances and family tree), biochemical, serological, imaging and endoscopy data were collected on the proforma (as given in detail in Table 1, Table 2, Table 3 and Figure 2). In the testing circumstances for screening, an umbrella term “etiological work up of liver disease” was defined as HBsAg detected during the work up of the clinical features suggestive of liver disease (jaundice, ascites, upper gastrointestinal bleed or splenomegaly), or abnormal liver function tests [raised bilirubin and/or aspartate aminotransaminase and/or alanine aminotransaminase (ALT) and/or alkaline phosphatase] or an abnormal liver scan (coarse echotexture and/or nodular, small, shrunken liver or mass). Hepatitis B-related serological data were recorded in the form of quantitative HBV-DNA level (IU/ml) and HBeAg (positive or negative).
Table 1Demographic Parameters of Patients in Various Clinical and Natural History Phases.
Variables
Overall (n = 421, 100%)
IDAHB (n = 303, 71.9%)
HBWAS (n = 31, 7.3%)
AHB (n = 3, 0.7%)
CHB (n = 92, 21.8%)
Cirrhosis (n = 87, 20.6%)
Age (mean ± SD, years)
36 ± 14.5
34 ± 14.4
35.3 ± 14.7
37.3 ± 14.7
31.9 ± 13.4
40.4 ± 14.5
Gender (Males, %)
301 (x = 71.5)
202 (x = 66.6, y = 67.1)
25 (x = 80.6, y = 8.3)
2 (x = 66.6, y = 0.6)
63 (x = 68.4, y = 20.9)
58 (x = 66.6, y = 19.2)
Abbreviations: AHB, acute Hepatitis B; CHB, chronic hepatitis B; HBWAS, hepatitis B with acute symptoms; IDAHB, incidentally detected asymptomatic hepatitis B.
The data were exported to Microsoft excel sheet for analysis. Continuous data were summarised as mean ± standard deviation, whereas categorical in number and percentage (%). After analysis, the data were represented as tables and figures. In tables, row percentages were expressed as x and column percentages as y.
Results
Development of a Diagnostic and Therapeutic Algorithm for HBsAg Positive Patients
Based on the above work up plan and terminologies used, we developed KGHeBTA , a comprehensive diagnostic and therapeutic algorithm (Figure 1). It suggested a simple follow up plan also.
Description of Study Flow Chart
The data of 1508 HBsAg-positive patients from outdoor record database were identified. Four hundred twenty-one HBsAg-positive patients had complete records. 1087 patients were excluded due to reasons given in Figure 2. Approximately one-fifth (85/421, 20.1%) cases were eligible for oral antivirals as per the diagnostic and therapeutic algorithm (Figure 2). 49 patients from the not eligible category were treated with antivirals due to special indications. Among these, 5 had pregnancy, 6 had a strong family history, 1 developed cirrhosis on subsequent imaging and 1 patient crossed 30 years limit, so were included into the eligible category. Rest in 36 patients, no reason for starting treatment was recorded. Thus, overall 134/421 (32%) patients were treated with antivirals in this study. Among antivirals, tenofovir was used in 112/134 (84%), tenofovir alafenamide in 17/134 (13%), entecavir in 4/134 (3%) and lamivudine plus tenofovir in 1/134 (0.01%) patient. Nineteen (4.5%, i.e. 0.9% per year) patients lost HBsAg during the study period. Two patients (0.004%) had HCC.
As shown in Figure 2, Figure 3, 221 (52.4%) patients had detectable baseline HBV-DNA, 154 (36.6%) had undetectable HBV DNA and in 46 (11%) HBV DNA was not available. Non-cirrhotics were higher than cirrhotics (336, 79% versus 85, 21%). In the non-cirrhotic group, the highest number of cases were in the IDAHB group (303, 72%), while lowest were in the AHB group (3, 0.7%). CHB with detectable HBV-DNA had various sub-stages in frequencies, as given in Figure 3. Those with undetectable or not available HBV-DNA were not classified further due to futility.
Figure 3A bar diagram showing comparative frequencies of various natural history phases in those with detectable baseline deoxyribonucleic acid versus not detectable/not available (HBWAS; Hepatitis B with acute symptoms, IDAHB; Incidentally detected asymptomatic hepatitis B, AHB; Acute hepatitis B, CHB; Chronic hepatitis B, LTFU; Lost to follow up).
Among all, 72% patients were males and 28% were females. Males also predominated all the stages of hepatitis B. The mean age of the study population was 36 ± 14.5 years with a range between 6 and 79 years. Cirrhotic patients had higher age as compared to others (40.4 ± 14.5 versus 34 ± 14.4, 35.3 ± 14.7, 37.3 ± 14.7 and 31.9 ± 13.4 years) (Table 1).
Testing Approaches (Circumstances)
In our study, HBsAg-positive patients were mostly detected while screening during medical illness (40%), followed by the etiological work up of liver disease (23%), unknown reason (13%), pre-surgical screen (10%), pregnancy (6%), visa clearance (4%), family screening due to a HBsAg positive family member (3%), blood donation (2%) and health camp (0.2%), as described in detail in Table 2. IDAHB was the most common stage in all testing circumstances except when HBsAg was detected during the etiological work up of liver disease, where cirrhosis predominated (60.9%).
Risk Factors
The main risk factors for HBsAg infection in our study were road-side shave (52%) followed by surgery (34%), dental extraction (25%), tattooing (16%), blood transfusion (10%) and intravenous drug abuse (0.2%). The distribution of the various risk factors according to clinical substages is given in detail in Table 3. IDAHB was the most common and AHB was the least common stage associated with all risk factors. Till around three decades ago, blood banks did not screen blood or blood products for any viral markers. With the rising awareness of transfusion-associated hepatitis, the blood bank regulatory authorities have become strict for viral marker screening. Most of the authorised blood banks nowadays perform HBsAg screening of all blood products. So blood transfusion as a risk factor for HBV transmission is expected to reduce or become negligible now and in future.
Discussion
This study was conducted to develop a simple, comprehensive diagnostic and therapeutic algorithm for hepatitis B and to investigate the clinico-epidemiologic spectrum of hepatitis B patients at a tertiary care centre of the North Indian population.
Algorithm
The algorithms for the treatment of hepatitis B, given by various scientific societies, are either not composite or do not incorporate natural history phases in them.
The WHO algorithm defers treatment in both HBV DNA <2000 IU/ml and 2000–20000 IU/ml with persistently abnormal ALT without any rationale. Although we did not study immunoglobin M and immunoglobin G anti-HBc, liver stiffness measurement (FibroScan) and liver biopsy in our patients, these have been of proven benefit in deciding the stage and treatment with antivirals.
So, we have incorporated these in our recommended algorithm (KGHeBTA). Most of the investigations incorporated in the algorithm are nowadays available at the primary or at the most secondary care level. So this study and algorithm have widespread applicability. Since this algorithm is derived from the standard existing guidelines, no new category of patients were included for giving antiviral or to monitor further.
Natural History
Over the past four decades or so, our understanding of the natural history of CHB has greatly evolved. New studies continue to provide new information about the differences in serological markers between different phases of the disease. The natural history study is essential not only to understand the outcome of chronic HBV infection but also to understand which factors contribute to the progression of the disease and when it makes sense to intervene with antiviral therapy to prevent the development of cirrhosis, HCC and death. As soon as HBV infection has been established in a host, the clinical illness can take one of two courses: first, acute infection and then chronic infection. The natural history of HBV infection is affected by HBV (HBV genotype, HBV-DNA level and viral mutations), host (gender, family history and age of infection) and environment (alcohol, NAFLD, co-infection with HCV, HIV and HDV).
In the present study, the HBV-infected patients were divided into five groups: IDAHB, HBWAS, AHB, CHB and cirrhosis on the basis of their clinical presentations. IDAHB were highest in number in our study. Deciding the stage of a patient is important to decide whether to start treatment or monitor only. This is the first study providing large-scale data, describing various stages from our region. In an earlier study, among 70 patients, 32 (46%) were chronic hepatitis and 38 (54%) were cirrhosis. HBeAg (n = 67) was positive in 50 (71%) and negative in 17 (24%). The study did not describe the proportion of acute cases and other subgroups of CHB.
Our study revealed that only approximately one-fourth of all included HBsAg-positive cases were treated with oral antivirals. This is novel data from our region given by our study.
Definition of AHB
It is routine to label patients presenting with jaundice, with prodrome as AHB but truly they may be any of either AHB, acute exacerbation of CHB or acute on chronic liver failure. So to avoid this confusion, a new term HBWAS is used in our study, which may be classified further on follow up as per the algorithm. Hepatitis B infection is considered resolved if HBsAg is cleared and antibodies are acquired to HBsAg. About 1% of patients clear HBsAg yearly, and most will also develop antibodies to HBsAg (anti-HBs).
In our study, 4.5% (0.9% per year) patients lost HBsAg, which is similar to others.
Testing Approaches (Circumstances) of Detection
HBsAg was mostly detected in either screening in hospitals for various indications, during visa clearance or family screening. The role of active case detection in the form of campaigns was minimal. Seeing the results of our study, the WHO goal “Eliminate viral hepatitis by 2030”
appears to be a far-fetched dream. Population-based active disease screening and surveillance program are needed.
Risk Factors
Infected individuals carry HBV in their peripheral blood and other body fluids and any exposure to them can be a risk for transmission of the disease to non-immune and non-infected individuals. The routes of transmission vary significantly in different countries.
In the present study, roadside shaving (52%), surgery (34%), dental extraction (25%), tattoos (16%) and blood transfusion (10%) were the most prominent risk factors for HBsAg positivity. This was similar from the previous study by Patwa AK et al. for hepatitis C.
Previous history of surgery in females and roadside shaving in males are the commonest risk factors for hepatitis C infection: a cross-sectional retrospective study.
There may be several reasons for the wide variation in the route of transmission in different studies, e.g. heterogeneity in the conduct of studies, sociocultural practices, etc. Retrospective studies like ours cannot certainly confirm a causative association of the risk factors for HBV infection. For this, we need multicentre prospective cohort studies including various sociocultural practices.
Strengths, Limitations and Scope for Future Research
Our study provides a comprehensive diagnostic and therapeutic algorithm “KGHeBTA” for hepatitis B. It may guide clinicians in day-to-day practice. It is a cocktail based on the standard existing guidelines. Its limitation is that it talks about the treatment of naïve patients only and does not give a guideline for handling treatment-experienced HBsAg-positive patients. Another limitation is that it was validated in a retrospective cohort of the variable duration of the follow up data (6 months follow up data were studied to make the data homogeneous and to study natural history phases). Validation in a prospective cohort may be planned in further studies of the homogeneous and longer duration of follow up data. Ours is one of the largest databases of its kind from our region. There are few other limitations in our study. The datasheets of 1065 out of 1508 enrolled patients were incomplete. Among 421 patients with complete data, 111 patients were lost to follow up. Further research is needed to find out reasons for the loss to follow up because implications may be multiple. Although HBsAg loss was composite of the whole study duration, only six months follow up data after the enrolment of patients were analysed and presented. It gives only a limited overview of the natural history of the disease. Liver biopsy and liver stiffness measurement (FibroScan) were not done, so a lot of borderline/indeterminate cases would have been debarred from treatment timely. Ethnicity and various others sociocultural practices contributing to the risk of transmission of HBV were not assessed in our study that can be addressed in further studies. Still in a resource constrained setting, this study provides a useful database for further research.
To conclude, our study provides a comprehensive diagnostic and therapeutic algorithm “KGHeBTA” for hepatitis B. It also provides a valuable database from North India for the various stages of hepatitis B, testing circumstances for the detection of HBsAg, the risk factors for HBV transmission and the proportion of treated versus not treated by anti-HBV drugs. From our study methodology, the natural history of chronic HBV could be accurately concluded. This study can guide various large population-based programs in several ways, e.g. day-to-day treatment, planning funds for drug purchase, test kits and population-based screening programs etc.
Credit authorship contribution statement
Ajay Kumar Patwa: Data collection, Writing - original draft, Conceptualisation, Methodology, Supervision, Formal analysis and critical revision of the manuscript. Amardeep: Data collection and Writing - original draft of the manuscript. Pratishtha: Data analysis. Amit Goel: Critical review of the manuscript. Sumit Rungta: Data curation and Writing - original draft of the manuscript. Kamlesh Kumar Gupta: Data curation and Writing – original draft of the manuscript. Sanjeev Kumar Verma: Data curation and Writing - original draft of the manuscript. Virendra Atam: Critical review of the manuscript. Anil Gangwar: Data analysis and Writing - original draft of the manuscript. Ankur Yadav: Writing - original draft of the manuscript. Bhaskar Agrawal: Data curation and Writing - original draft of the manuscript.
Conflicts of interest
All authors have none to declare.
Acknowledgement
We like to thank the staff of the endoscopy lab of the Department of Medicine for their active contribution in data collection and handling.
Funding source
The study was not funded by any authority.
References
The World Health Organisation
Guidelines on hepatitis B and C testing.
(Guidelines on hepatitis B and C testing)2017: 1-170
Previous history of surgery in females and roadside shaving in males are the commonest risk factors for hepatitis C infection: a cross-sectional retrospective study.
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