Hepatitis B virus-induced hepatocellular carcinoma: a persistent global problem

Abstract

Hepatitis B virus (HBV) infections are highly prevalent globally, representing a serious public health problem. The diverse modes of transmission and the burden of the chronic carrier population pose challenges to the effective management of HBV. Vaccination is the most effective preventive measure available in the current scenario. Still, HBV is one of the significant health issues in various parts of the globe due to non-response to vaccines, the high number of concealed carriers, and the lack of access and awareness. Universal vaccination programs must be scaled up in neonates, especially in the developing parts of the world, to prevent new HBV infections. Novel treatments like combinational therapy, gene silencing, and new antivirals must be available for effective management. The prolonged infection of HBV, direct and indirect, can promote the growth of hepatocellular carcinoma (HCC). The present review emphasizes the problems and probable solutions for better managing HBV infections, causal risk factors of HCC, and mechanisms of HCC.

Introduction

Viral hepatitis is a severe liver infection affecting large segments of the world population. The hepatitis B virus (HBV) is one of several hepatitis viruses {hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV)} which are significant contributors to viral hepatitis[1, 2]. All these viruses produce similar symptoms and clinically cannot be differentiated. Laboratory diagnostic assays are required for the correct and assured diagnosis of viral hepatitis [3]. HBV infection affects the normal functions of the liver and causes inflammation, known as hepatitis. Liver cancer or hepatocellular carcinoma (HCC) is the second most prevalent human cancer after tobacco-related cancer. Viral hepatitis is accountable for up to 80% of cases of HCC worldwide, and most cases are of untreated HBV or HCV infection [1, 2, 4]. HBV infections can be broadly divided into acute and chronic categories of hepatitis infection. Clinical symptoms due to HBV infections have a broad range and vary from asymptomatic or mild to severe life-threatening [5]. Acute HBV infections are generally self-limiting, and only a few cases have acute inflammation or hepatocellular necrosis, with 0.5–1% of case fatality [5, 6]. Chronic hepatitis B (CHB) is less common than the acute form and does not lead to significant liver sickness in most cases. CHB may cause advanced liver fibrosis, cirrhosis, and HCC in some patients [7]. HBV is a ubiquitous virus. About one-third (> 2 billion) of the global human population has a history of HBV infection in their lifetime[8–10]. The majority of these HBV patients are recovering without any noticeable damage. About 350 million people are chronically HBV-infected and act as the carrier by spreading the infection to a vulnerable population [2]. HBV is a dangerous virus accountable for 4 million acute clinical cases annually. HBV is a reason for about one million deaths due to chronic active hepatitis, cirrhosis, or liver cancer [2]. World Health Organization (WHO) estimates that cirrhosis and HCC caused by HBV were responsible for more than 820,000 deaths globally in 2019 [2]. The present review emphasizes the problems and probable solutions for better managing HBV infections, causal risk factors of HCC, and mechanisms of HCC.

The virus and its life cycle

HBV belongs to the family Hepadnaviridae and contains a partially double-stranded DNA genome of about 3.2 kb, covalently linked to the viral polymerase. HBV is an enveloped virus of 42 nm in diameter. It has an inner nucleocapsid region (27 nm in diameter) composed of hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg). The host-driven lipid envelope of HBV contains surface antigen (HBsAg), which helps in the binding of HBV to receptors of hepatocytes [5, 11]. HBV binding and entry into hepatocytes have not been clearly understood, but experiments showed that it might be through endocytosis [12–14]. Various hepatocyte receptors proteins like transferrin, asialoglycoprotein, immunoglobulin A receptor, and human liver endonexin receptor were proposed as binding receptors for HBV [12–16]. Past studies showed sodium taurocholate co-transporting polypeptide (NTCP) as the potential receptor for HBV, which also acts as a significant species determinant specificity [17]. Only the nucleocapsid part of HBV enters the cytoplasm, which reaches into the nucleus via a nuclear pore and delivers viral DNA into the nucleoplasm (Fig. 1) [13]. HBV has partially double-stranded DNA, converted into a covalently closed circular (ccc) super-coiled DNA molecule inside the host nucleus [11, 18]. This cccDNA of HBV is transcribed into four important viral RNAs of different genomic lengths; a 3.5-kb RNA coding for polymerase and pre-core protein, 2.4- and 2.1-kb RNA coding for surface protein, and 0.7-kb RNA coding for regulatory X protein. HBV produces polyadenylated RNA, which is transported from the nucleus to the cytoplasm of the hepatocyte through the nuclear pore before translation. The 3.5-kb RNA, termed pre-genomic RNA (pgRNA), codes for core proteins and reverse transcriptase (RT) and also acts as a template for viral DNA synthesis [19, 20]. The nucleocapsids are synthesized in the cytoplasm and matured into DNA-containing nucleocapsids, which are imported either into the nucleus for cccDNA amplification or into the endoplasmic reticulum (ER) and released as progeny viruses [20]. Inside the endoplasmic reticulum lumen, mainly amino and carboxy-termini are trimmed, and the resultant proteins are secreted as the hepatitis B pre-core antigen (HBeAg) and surface antigen (HBsAg) (Fig. 1). The X protein determines the efficiency of HBV replication by interacting with various transcription factors and can stimulate cell proliferation and cell death [21]. Viral polymerase enzyme is multifunctional and involved in multiple viral activities like priming, polymerase and nuclease activity, and packaging of RNA pre-genome into nucleocapsids [22, 23]. Nuclear localization signals on polymerase mediate covalently linked HBV genome transport through the nuclear pore [23, 24].

Fig. 1.

Life cycle of hepatitis B virus inside a hepatocyte

Transmission

HBV can be transmitted through three transmission modes; parenteral/percutaneous, sexual, and perinatal/mother-to-child [8, 25–27]. The parenteral/percutaneous mode of transmission is the most common in which HBV spread through contaminated blood and other body fluids like saliva, semen, and menstrual or vaginal fluid [28, 29]. HBV can be transmitted from the accidental exchange of contaminated blood or other body fluids during medical, surgical, and dental procedures. Injection drug abuse remains a significant transmission mode in the USA and Western Europe [30–32]. Parenteral/percutaneous transmission can also occur during acupuncture, body piercing, scarification, and tattooing [33, 34]. HBV is categorized as a sexually transmitted disease (STD) and spreads from an infected person to an unvaccinated or susceptible person during homosexual or heterosexual activities. In countries with low and intermediate prevalence, sexual contact is the primary cause of HBV infection [35, 36]. HBV infection can be transmitted through the perinatal mode from HBeAg seropositive mother to their neonate without prophylaxis. The comparative risk of perinatal HBV infection is more if the mother has become acute HBV positive in the later stage of pregnancy than in the early stage. The infection rate increases if the mother is positive for both HBeAg and HBsAg. HBV infection spreads during delivery or after birth due to placental tears and hemorrhages [37]. There is no experimental evidence that HBV transmits through breast milk. Perinatal spread of HBV is a standard route in China and South-East Asian countries. In neonates and children (less than 1 year old) infected through perinatal mode, the risk of CHB infection is 90% [38, 39].

Prevalence

On a global scale, the HBV attack is not uniform. The population comes under three broad categories based on the prevalence of disease, viz., high (> 8%), higher intermediate (5–8%), lower intermediate (2–5%), and low (< 2%) [28, 36]. Figure 2 shows the HBV virus’s global prevalence based on the HBsAg distribution. The regions with high endemicity include countries of Asia–Pacific and sub-Saharan Africa. Most African countries have high or intermediate endemicity [40]. About 70–90% of the adult human population from these areas is HBsAg seropositive, out of which about 8–20% serve as HBV carriers [41, 42]. In a higher intermediate endemic country like the Republic of China, the occurrence of chronic hepatitis B is very high in newborns (90%) and young children (30%) infected with HBV [43]. The parts of the world, including Southern Europe, the Middle East, South Asia, Russia, Japan, and South America, are categorized into the region of low intermediate (2–5%) to low (< 2%) endemicity. About 10–60% of the population in these areas is infected, of which 2–7% serve as carriers[44, 45]. In India, about 2–8% of the population have HBV infection, and about 3% act as a carrier [46]. Developed parts of the world, like North America, Australia, New Zealand, and some portions of Europe and South America, have a low prevalence of HBV [40, 47]. The prolonged infection of HBV, direct and indirect, can promote the growth of HCC, a major reason for global mortality.

Fig. 2.

Global prevalence of hepatitis B virus (adapted from Schweitzer et al. 2015)

Risk groups for HBV and HCC

Susceptibility to HBV infection depends upon many personal factors like age, nutritional standard, and immunization status of patients. Risk groups for HBV infection include injection drug users, healthcare persons, patients undergoing surgery, hemodialysis or blood transfusions, people having homosexual activities or heterosexual activities with multiple sex partners, and neonates born to chronic carrier mothers or mothers having acute HBV infection during pregnancy [33, 48, 49]. CHB is a persistent problem in neonates delivered by HBeAg-positive mothers, and the severity of infection decreases in them with age (20–60% under 1–5 years and < 5% in adults) [50, 51]. Immunity against a specific disease can be developed through effective vaccination or infection recovery. Immunocompromised or immunosuppressed people are at more risk of HBV infections [52]. A patient’s age is an essential factor in determining the severity and outcome of HBV infection. CHB is highly prevalent in neonates up to six months of age [38, 39]. Although the liver has the highest regeneration power, the age and nutritional status of the patient also play an essential role in recovery from viral hepatitis infections. Various factors responsible for HCC due to chronic viral hepatitis include gender (hepatocellular carcinoma is much more common in men than women), race/ethnicity, cirrhosis, inherited metabolic diseases, heavy alcohol use, tobacco use, and obesity.

HBV and liver cirrhosis

Liver cirrhosis is a progressive stage of liver infection that may occur due to various reasons, including the conditions of HBV or HCV infection, alcoholism, and autoimmune diseases. The presence of more than one factor may cause more dangerous liver cirrhosis [8, 53]. During HBV infection, hepatocytes may gradually be damaged and lead to scar formation. The initial stage of liver damage is called fibrosis, which leads to a severe condition known as liver cirrhosis. Unfortunately, most patients do not experience any unusual symptoms until full-blown cirrhosis or end-stage liver disease. Therefore, they do not get early and effective treatment, which worsens the situation [54]. Liver transplantation is the only solution available for end-stage cirrhosis patients. Cirrhosis and hepatocellular carcinoma (HCC) are significant reasons for premature death in 25% of HBV patients who get infected in childhood, while 15% die from these diseases who got HBV infection after childhood [6, 55].

Detection of HCC and HBV

In addition, early detection of HCC is a significant barrier. In recent times, the early identification of HCC has centered on surveillance through ultrasonography (US) [56], and alpha-fetoprotein serological tests (AFP) [57]. However, the specificity and sensitivity of the US and AFP are not adequate for the diagnosis of HCC. Also, Recent technological advances offer hope for HCC detection at an early stage. The tests used to diagnose HCC generally involve cross-sectional diagnostic imaging, serological diagnosis, and histological diagnosis. Cross-sectional diagnostic imaging, such as ultrasound (US) [56], computed tomography (CT), and magnetic resonance imaging (MRI), is indispensable not only for the diagnosis of hepatocellular carcinoma (HCC) but also for the assessment of tumor staging and therapeutic response [58]. In serological diagnosis, various types of biomarkers are used for detection. They may be proteinous and mRNA-type biomarkers in nature. Some of them are like, alpha-fetoprotein (AFP) has emerged as a most promising and well-studied biomarker candidate. Dysregulated levels of AFP in the plasma strongly correlate with HCC malignancy. Some mRNA and protein biomarkers are alpha-fetoprotein (AFP), AFP-L3 [59], Protein induced by vitamin K absence II (PIVKA II) [60], Glypican-3 (GPC3) [60], Golgi protein-73 (GP73) [61], Osteopontin (OPN) [62], Dickkopf-1 (DKK-1) [63], lncRNAs, etc. while various are in progress.

In recent times, the concept of “liquid biopsy” has attracted a significant deal of interest and revolutionized the area of tumor diagnostics. Circulating DNA (ctDNA) and circulating tumor cells are important markers for measuring liquid biopsies [64]. Although other biomarkers are being developed. To effectively screen, diagnose, and subsequently treat individuals who are diseased with HBV, it is vital to know the current diagnostic tests. HBV infection is indicated by the presence of HBsAg, anti-HBs, HBeAg, anti-HBe, and anti-HBc IgM and IgG antibodies [65]. The development of serological markers permits the identification of patients infected with HBV. Many serological methods, including radioimmunoassay, enzyme immunoassay, Electrochemiluminescence immunoassay, chemiluminescence immunoassay, micro-particle enzyme immunoassay, and chemiluminescence immunoassay might be used [66]. As in the technique of molecular detection, HBV DNA provides a direct assessment of viral load, revealing the multiplication activity of the virus. It may be detected at an initial stage of infection. The detection of HBV DNA is a great marker of replication activity, and larger titers of HBV DNA are associated with a more rapid course of the illness and an increased risk of HCC. Reverse hybridization, genotype-specific PCR tests, real-time PCR, restriction fragment-length polymorphism, Loop-mediated isothermal amplification assay, sequence analysis, microarray (DNA Chip), and fluorescence polarization assay may be used to validate HBV genotyping [67–69]. Also, the Identification of HBV genotype, HBV mutations, and other prognostic markers enables tailored therapies and risk-surveillance methods, such as hepatocellular carcinoma screening. In the future, these characteristics may allow classification not just of treatment options, but also of individuals at increased risk of recurrence when current medications are terminated. In the majority of the country, Hepatitis viral infection is diagnosed through biochemical assay specifically liver functional test. Most of the cases recover without much significant damage to their liver, some cases convert into liver cirrhosis or HCC. Liver cirrhosis and HCC detect in the later stage when their treatment is very difficult.

Mechanism of HCC due to HBV

Some patients with persistent infection of chronic HBV may develop hepatocellular carcinoma (HCC) or liver cancer. CHB is the primary factor responsible for HCC in the HBV-endemic regions of the world [70–73]. Worldwide, liver cancer is annually accountable for more than one million deaths. HCC is a dangerous and drastic type of disease, the seventh and ninth most prevalent respective cancer in male and female patients. Comparatively, male patients with CHB are at more risk of developing HCC than female patients due to their male hormones [73–75]. Geography, race, age, gender, obesity, alcoholism, and family history are important variables associated with the HCC [76, 77]. The geographic distribution pattern of HCC is related to the frequency of persistent HBV infection. In developing parts of the world, like Africa and East Asia, HBV is the major contributor (60–80%) of liver cancer. In contrast, about 20% of the HBV cases in developed countries contribute to HCC [78, 79]. The diagnosis of HCC can be made by specific cancer markers like serum alfa-fetoprotein (AFP) and by diagnostic imaging of the liver using ultrasound imaging, computed tomography (CT) scan, or magnetic resonance imaging (MRI) [80].

In HBsAg carrier patients, regular check-ups of their liver should be done by these methods at least once every six months. Treatments like surgery, hepatic irradiation, and anticancer drugs are available to treat liver cirrhosis and cancer patients [81]. Hepatitis B virus infection is one of the most significant risk factors for hepatocellular cancer (HCC). Currently, it is considered that HBV-induced HCC is the result of a complicated interplay between viral components and various host factors. Several pathways are believed to be involved in the pathogenesis of HBV-induced HCC, such as HBV–DNA burden, HBV-DNA integration into host genetic machinery, immune-mediated inflammation, HBx protein, etc. [82, 83].

Chronic illness due to HBV results from its presence in the host cells for a long time via various mechanisms that include infection of immune defense control centers, viral inhibition of antigen presentation, selective immune suppression, down-regulation of viral gene expression, and viral mutations. It functionally incapacitates virus-specific T cells from recognizing HBV antigen, and such cells ultimately survive the virus for a long period [84]. People with HBV infection are more likely to get HCC depending on several factors, but HBV–DNA levels are the most significant. When there were 10,000 copies of HBV-DNA per milliliter, the chance of getting HCC went up a lot. People whose HBV–DNA load was below the lower limit of detection (LOD) (300 copies/ml) were half as likely to get HCC as people with viral loads of 10,000–100,000 copies/ml and people with viral loads of > 100,000 copies/ml were six times as likely to get HCC [85, 86]. HBV DNA gets integrated with the human genome, which leads to changes in several genes and ultimately affects cell growth, division, and survival. C-terminal truncated HBx, which is a result of HBV integration, has been emphasized for its role in the development of HCC [87]. Apart from being involved in many intracellular signaling pathways linked to cell growth and death. HBx is a major factor in the development of HCC through direct as well as indirect mechanisms, even though it is not directly linked to cancer progression.

All mammalian hepadnaviruses have a very similar phylogeny, which suggests that the HBx gene, which codes for the HBx protein, is very important to the virus’s life cycle. This gene has 452 nucleotides while the encoded HBx protein is 17 kDa in size and 154 aa in length. HBx protein has many different roles, (as shown in Fig. 3) in the host cell. It can modulate various cellular processes, including cell cycle progress, Apoptosis (effect on pro-apoptosis, and anti-apoptosis), DNA repair (impact on transcription factor IIH, base, human 8-oxoguanine DNA glycosylase 1, DNA glycosylase A and excision repair pathway through both p53-dependent and independent mechanisms), mutation (effect on C-terminal truncation point mutation), immune system (evasion chronic infection), epigenetics (methylation, and acetylation), signalling pathways (effect on notch pathway, PI3K/mTOR, Wnt/beta-catenin signaling pathway), transcriptional pathways like noncoding RNA (microRNA, and long noncoding RNA), cell proliferation, oxidative stress (effect on reactive oxygen species, and NAD(P)H: quinone oxidoreductase 1, Forkhead box class O 4), and genetic stability by interacting with different host factors [88, 89].

Fig. 3.

Various mechanism of HCC by HBV (HBx)

Immune and inflammatory responses induce cytokines and chemokines to be released, which leads to oxidative stress. This, in turn, leads to the constant activation of genes that cause cirrhosis, such as TERT, MLL4, RAR, CCNE1, Cyclin A2, FN1, ROCK1, SENP5, ANGPT1, PDGF receptor, calcium signaling-related genes, ribosomal protein genes, epidermal growth factor receptor (EGFR), and mevalonate kinase carboxypeptidase, which promote HCC proliferation and angiogenesis [90]. HBV products like proteins and mRNAs are involved in many other signaling pathways in hepatocytes. This affects the expression and function of certain genes and can lead to liver disorders. The majority of these alterations are attributable to HCC, and more research is ongoing.

Treatment and prophylaxis

HBV infections can be acute or chronic, and most acute infections are generally self-limiting and do not require specific treatments. There are no specific antivirals or medications for acute HBV; only supportive therapy can be given [91–93] Antiviral treatment is given to patients with chronic hepatitis B to prevent the progression of the disease. Steroid therapy is given to symptomatic patients of chronic HBV with severe histologic lesions in their liver biopsies [94]. Interferon therapy can be provided in CHB infections and acts as an immunomodulator but is generally associated with side effects. The efficacy of interferon therapy is higher in young patients than in aged ones [95]. Specific antiviral drugs such as adefovir, lamivudine, tenofovir, and telbivudine are available for CHB patients. However, antiviral therapy is associated with the risk of developing resistance after prolonged use [96]. Nutritional standards and effective antiviral medicines for HBV-positive patients determine the effective recovery of CHB patients.HBV vaccines are used mainly as the primary prevention to reduce the risk of HBV infection. The first plasma-derived HBV vaccine developed from HBsAg antigen inactivated with the help of urea, pepsin, formaldehyde, and the heat was introduced in 1982 [97]. Other HBV vaccine from recombinant yeast sources was also introduced until the mid-1980s [98]. Presently, recombinant DNA vaccines are being used in national vaccination programs and proving to be highly safe and effective in controlling HBV infections. Universal infant vaccination programs have been carried out worldwide [99]. HBV vaccines are most effective when given early, and antibody response rates decline gradually after 40 years of age [99, 100]. Previous studies proved that the protective effects of HBV vaccination might continue for at least 10 to 15 years or even beyond 15 years in some cases[101–103].

Challenges of HBV and HCC

HBV can be transmitted through various routes like parenteral, perinatal, and sexual, which increase the chances of the virus spreading and pose challenges in controlling the outbreak. Vaccination is available against HBV and is effective in 95% of HBV cases. However, the remaining 5% of vaccinated individuals failed to develop immunity, and the mechanism of this non-response to the HBV vaccine is not fully understood yet [104–106]. Underlying medical conditions such as CHB, HIV infection, hemodialysis, immature neonates, age, and immunosuppression are some factors that seem to be associated with non-response to the HBV vaccine [10]. Most CHB patients remain asymptomatic and are not diagnosed with HBV, but they still threaten infection transmission. All HBsAg-positive carriers serve as the potential source of HBV infection. Large segments of the world population are HBV-positive and act as the carrier, making controlling the disease more challenging [6, 8, 107]. Mother-to-child transmission of HBV is still a common mode of infection in developing parts of the world. About 10% of the children born to infected mothers still have CHB infection despite vaccines [108, 109]. HBV can be diagnosed by rapid commercial, immunological, and modern molecular assays. A good array of diagnostic assays are available, but their distribution is not equal [110–112]. Developing regions of the world still require rapid, sensitive, specific, and cost-effective diagnostic assays to effectively screen HBV-infected populations. More than 75% of the world population lives in hyper-endemic areas of HBV, which provide an easy chance of HBV transmission between infected and susceptible persons [113–115]. HBV carrier people are clinically asymptomatic and may spread the infection for a long time without knowing. Occult HBV infection is another problem in which screening tests based on HBsAg failed to detect the infection due to a very low copy of the virus. Occult HBV infections can be categorized into seropositive and seronegative infections based on the detection of antibodies against HBcAg and HBsAg. About 20% of occult HBV infections are seronegative and are challenging to diagnose [116]. PCR-based detection of HBV DNA is the only reliable method for detecting these infections. Many occult HBV infections go undetected, further spreading infection in the healthy population [115].

Opportunities

Vaccination is considered the major prophylactic measure to reduce the mortality caused by HBV infection in healthy patients. The effectiveness of HBV vaccination can be increased by changing the route of administration. The conventional intramuscular (IM) route of the HBV vaccine, when replaced with intradermal (ID) administration after every two weeks, induces 94% anti-HBV response in previously nonresponder individuals [117]. Recombinant vaccines observed seroconversion in the healthcare worker group at a rate of 95.5% via ID and 85% via IM routes [118]. The intradermal route of vaccination has shown better responses to HBV than conventional intramuscular route vaccination in certain special groups like healthcare workers, dialysis patients, immunocompromised (HIV-infected) patients, and in patients with celiac disease [118–124]. There is a positive impact of hepatitis B recombinant vaccine on immune response in more than 90% of the normal population [125]. On the other hand, despite the staggering response of commercial antivirals, the long-term medication and secluded persistence of the virus in hepatocytes remain a big challenge. Researchers have devised various strategies to tackle these problems, such as identifying novel drug targets, employing the concept of trained immunity, genome editing, and gene therapy. Immense research on novel drug targets for HBV therapy includes nucleoside inhibitors, immune stimulants, and viral entry inhibitors. Immune stimulant molecules are screened that elicit a potent innate immune response [126]. Identified dynamic targets of the immune system mainly consist of pattern recognition receptors and Toll-like receptors [127, 128] 2, 4-Diaminoquinazolines is one such potent Toll-like receptor agonist that shows promising activity in vivo that produces an optimum cytokine profile [129]. Another target for antiviral development is a viral entry inhibitor, which helps reduce the intrahepatic spread of infection. These molecules target NTCP, a leading receptor for viral entry [130, 131]. Myrcludex B is a synthetic N-acylated lipopeptide that showed promising activity in blocking receptor activity, both in vitro and in vivo[132]. Advanced studies on universal antiviral therapy for HBV are based on using ex vivo techniques to engineer the genome of viruses. Modern techniques like CRISPR/Cas9 system enable cleavage by targeting the specific genes of the Virus [133]. A research group proposed targeting the covalently closed circular DNA of the virus using the CRISPR/Cas9 system [134]. Medicinal plants are an excellent alternative to combat the HBV burden as they pose very natural and economical means with few side effects and require low technical expertise. Available HBV therapies have feeble efficiencies in long-term usage with many adverse side effects and limitations in the form of resistance in the case of long-term treatments [135]. Therefore a sensitive, safe, and cost-effective anti-HBV therapy is needed. Worldwide, herbal medicine formulations have a long history of their capability to cure liver infections [136, 137]. Numerous medicinal plants have anti-HBV potential, which must undergo in vivo clinical trials before being used as therapeutics. Oenanthe javanica, Curcumin, and Phyllanthus species are well-documented medicinal plants having anti-HBV properties [138, 139]. Thus, the efficacy of these and other similar medicinal plants against HBV is explored by modern research to replace conventional synthetic and harmful drugs. Acanthus ilicifolius L. can reduce HBV-induced liver damage by suppressing the activity of enzyme transaminase [140]. Phyllanthus extracts show a reduction in HBV DNA synthesis and secretion of HBsAg and HBcAg in infected hepatocytes [141]. This may be due to the induction of β-interferon, cyclooxygenase-2, and interleukin-6 through the activation of signal-regulated kinases and c-jun N-terminal kinases [142]. Phytochemicals like glucopyranosides and flavones obtained from Alternanthera philoxeroides exhibited significant anti-HBV activities in the cell culture model [143]. Active components (oxymatrine, artemisinin, artesunate, and wogonin) from traditional Chinese medicinal plants have potent anti-HBV activities [144]. There is enormous information in the Indian Ayurvedic system, Chinese traditional medicines, and modern medical science that claims various medicinal plants’ effectiveness against many viruses.

Conclusion

HBV is a major pathogen responsible for viral hepatitis and is associated with considerable morbidity and mortality worldwide. Although HBV is much improved in developed parts of the world, the population living in endemic developing countries is still the major reservoir of the virus. CHB and HCC are also serious problems related to HBV, which can be controlled effectively by using universal vaccination programs. Better management of HBV infections can be achieved through increased vaccination among risk groups, awareness campaigns, effective surveillance of the carrier population, and the development of cost-effective diagnoses and treatments. More effective HBV screening and surveillance measures should be devised, especially for CHB infections. More emphasis is needed on research that improves the impact and coverage of the current vaccination program. More inputs are required in gene silencing technology development of antiviral and novel therapeutic Phyto-compounds to eradicate the HBV problem.

Author contribution

Sanjit Boora, Vikrant Sharma, and Samander Kaushik have performed the conception or design of the study. Samander Kaushik, Sulochana Kaushik, Ajoy Varma Bhupatiraju, and Sandeep Singh in editing, acquisition, analysis, or interpretation of the data.

Data availability

Not applicable.

Declarations

All data relevant to the study is included in the article.

Ethical approval

NA.

Conflict of interest

The authors declare no competing interests.