Current perspectives of viral hepatitis

Abstract

Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. The five liver-specific viruses: Hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis D virus, and hepatitis E virus, each have their own unique epidemiology, structural biology, transmission, endemic patterns, risk of liver complications, and response to antiviral therapies. There remain few options for treatment, in spite of the increasing prevalence of viral-hepatitis-caused liver disease. Furthermore, chronic viral hepatitis is a leading worldwide cause of both liver-related morbidity and mortality, even though effective treatments are available that could reduce or prevent most patients’ complications. In 2016, the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by the year 2030, along with a discussion of current gaps and prospects for both regional and global eradication of viral hepatitis. Today, treatment is sufficiently able to prevent the disease from reaching advanced phases. However, future therapies must be extremely safe, and should ideally limit the period of treatment necessary. A better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis. This review aims to summarize the current state of knowledge on each type of viral hepatitis, together with major innovations.

Key Words: Hepatitis A virus; Hepatitis B virus; Hepatitis C virus; Hepatitis D virus; Hepatitis E virus; Current perspectives

Core Tip: Viral hepatitis represents a major danger to public health, and is a globally leading cause of death. In 2016, the World Health Organization released its plan to eliminate viral hepatitis as a public health threat by 2030, alongside a discussion of current gaps and prospects for regional and global eradication of viral hepatitis. Today, treatment is sufficiently able to prevent the disease from reaching advanced phases. Moreover, a better understanding of pathogenesis will prove beneficial in the development of potential treatment strategies targeting infections by viral hepatitis. This review aims to summarize current knowledge on each type of viral hepatitis, together with major innovations.

INTRODUCTION

Viral hepatitis represents a major danger to public health, and is a globally leading cause of death[1,2]. The five liver-specific viruses: Hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV), each have their own unique epidemiology, structural biology, transmission, endemic patterns, risk of liver complications, and response to antiviral therapies. These viruses represent a significant worldwide public health danger, especially in places where they remains prevalent[3-5]. These are known as “hepatotropic” viruses, and are the causes of the majority of hepatitis in both the pregnant and non-pregnant populations[5]. Global viral hepatitis prevalence is very high, and appears to be continuing to rise over time[5]. Of these viruses, blood-borne hepatitis in particular, including HBV and HCV, is the global cause of significant morbidity and mortality[6].

Due to the highly effective prevention measures and treatments available, the elimination of viral hepatitis worldwide represents a realistic goal, and has been endorsed by all member states of the World Health Organization (WHO)[1]. The WHO’s ambitious targets call for a 65% reduction worldwide in hepatitis-related mortality, a 90% reduction in new infections, and access to key treatment services increasing to 80% of the population by 2030[1,2]. In addition to additional measures to increase availability of vaccinations and treatment, there is a need for more emphasis on increasing access to affordable, high-quality diagnostics, if testing is to reach the levels necessary in order to achieve goals related to the elimination of these viruses[1].

It is important to collect specific details regarding exposure to viral hepatitis, including travel, food preferences, drug use, and sexual activity[7]. Needlestick injuries can cause transmission of blood-borne pathogens, such as HBV, HCV, and HIV[8]. Viral hepatitis is a leading cause of liver tissue inflammation (hepatitis), and hepatitis has been demonstrated in the long term to lead to the development of hepatocellular carcinoma (HCC) and cirrhosis[9]. HBV and HCV are indirectly correlated with carcinogenesis, due to the way they can cause chronic inflammation in organs that have been infected[10]. In addition, the tumor microenvironment contains various immune cells, endothelial cells, and fibroblasts, as well as a number of growth factors, cytokines, and other tumor-secreted molecules that play key roles in the growth, progression, and migration of tumors, and these have a close interrelation with the virus[10]. Within the tumor microenvironment, the presence of T-regulatory cells and B-regulatory cells serves an important purpose in the anti-tumor immune reaction[10]. The immune microenvironments of tumors vary for each type of cancer, and are dependent on viral infection[10]. In cases involving pregnancy, it is vital to consider the mother’s liver health, the influence of pregnancy on the clinical course of the viral infection, and any effects the virus or the liver disease could have on the developing fetus[3]. Although all hepatitis viruses have the potential to harm both mother and child, acute HAV or HEV infections during pregnancy pose the greatest risk to maternal and, consequently, fetal health[3]. On the other hand, the primary risks for HBV, HCV, and HDV are related to the severity of underlying liver disease in the mother, and the risk of HBV or HCV being transmitted from mother to child[3].

Viral hepatitis is known for a wide spectrum of clinical presentations, ranging from a benign form that has few or even no symptoms, all the way to acute liver failure or death[11]. In addition, most cases of viral hepatitis during pregnancy are detected through related signs and symptoms (such as fatigue, abdominal discomfort, jaundice, or scleral icterus), or incidentally noted transaminitis on routine lab examinations[7]. Important principles for management of viral hepatitis include high levels of clinical suspicion, medical history reviews, and awareness of risk factors for acquisition of infection[7,12]. Survival rates following liver transplantation (LT) have increased dramatically over time, with significant post-LT survival improvements due to improvements in surgical techniques, peri-operative care, and optimal immunosuppressive therapy, as well as the availability of highly effective antiviral drugs[13]. Hospitalization is necessary for the majority of LT recipients, and this population has a mortality rate of approximately 20%[13]. Optimizing immunosuppression is an important step in reducing the severity of allograft damage when treating post-transplant viral infections, and early initiation of high-potency antiviral therapy can help achieve viral clearance or control[13].

Unfortunately, there are still few treatment options available, despite liver disease due to viral hepatitis becoming increasingly common[14]. In addition, managing these kinds of viral hepatitis has significant health-economic costs, and reducing their prevalence requires following prevention measures like vaccination programs, and improving hygienic conditions[4]. Pregnancy and interpregnancy care can offer chances to prevent hepatitis infections and transmission[15].

In order for metabolic factors to be identified as HCC risk factors in chronic liver disease patients with infections such as HBV or HCV, there should be strong synergistic interactions between the metabolic factors’ carcinogenic mechanisms and the chronic liver disease[16,17]. As a result, chronic viral hepatitis is a leading global cause of liver-related morbidity and mortality, despite effective treatments being available that can reduce or prevent most patients’ complications[18].

The characteristics of hepatitis viruses are shown in Table 1. This review aims to summarize the current knowledge on each type of viral hepatitis, including general information, epidemiology, etiology, mechanism, symptoms, examination, diagnosis, treatment, management, complications, and prognosis, together with major innovations, and detailed information is provided in the following section.

Table 1 Characteristics of hepatitis viruses.

Virus	Hepatitis A	Hepatitis B	Hepatitis C	Hepatitis D	Hepatitis E
Family	Picornaviridae	Hepadnaviridae	Flaviviridae	Deltaviridae	Calciviridae
Nucleic acid structure	Positive sense, single-stranded RNA	Circular, double-stranded DNA with single-stranded portions	Positive sense, single-stranded RNA	Negative-stranded circular RNA	Positive sense, single-stranded RNA
Genome size (kb)	7-9	3-4	10-12	1.7	7-8
Envelope	No	Yes	Yes	Yes	No
Epidemics	Yes	No	No	No	Yes
Route of infection	Fecal-oral, sexual, and parenteral	Blood, sexual, and parenteral	Blood, sexual, and parenteral	Blood, sexual, and parenteral	Fecal-oral, parenteral, and zoonotic
Examinations	Anti-HAV IgM in blood and stool	HBs antigen	Anti-HCV IgM, anti-HCV IgG	Anti-HDV IgM, delta antigen	Anti-HEV IgM
Course in pregnancy	Benign and self-limiting	Acute and chronic infections	Acute and chronic infections	Requires HBV coinfection for propagation	Acute
Risk of VT	Probable and rare	Yes, 30%, related to maternal VT	Yes, 3%-10%, related to maternal VT	Exceptional	Yes, 46%
Preventing VT	Avoid infection by public hygienic measures	Antenatal antiviral therapy; active and passive immunization to neonate	Reducing maternal VT with therapy	Reducing HBV VT	Avoid infection by public hygienic measures
Breastfeeding	Yes, safe	Yes, safe	Yes, safe	Yes	Not safe in acute phase
Infant follow-up	Not needed	Serology 3 months after completing vaccination course, usually at age 9 months	Anti-HCV testing at 12-18 months to clear passively transferred maternal antibodies	Not needed	Intensive monitoring of consequences for VT, if occurs
Vaccine	Yes	Yes	No	No	Two vaccines are in trial

VT: Vertical transmission; HAV: Hepatitis A virus; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HDV: Hepatitis D virus; HEV: Hepatitis E virus.

HAV

Globally, HAV is the most common cause of acute viral hepatitis[19]. Ironically, in areas with rapidly improving sanitary conditions, more and more adults lack immunity for HAV from early childhood, and as a result adults lacking this immunity are exposed to risks like symptomatic disease and large society-wide outbreaks[20]. Though hepatitis A has greater rates of spontaneous remission, there have been recent outbreaks attributable to vaccine shortages in dense urban areas with insufficient affordable housing, as well as a lack of access to sanitation, and changes in the epidemiology of viral strains, resulting in more and more hospitalizations and deaths[21].

Infection incidence is strongly correlated with low socioeconomic conditions and poor sanitary conditions[19]. A total of 53% of all outbreaks have been traced back to food handlers who were themselves infected, and food contaminated with HAV is responsible for 2%-7% of all HAV outbreaks internationally[22,23]. The extent of liver damage caused by HAV can range from mild illnesses to fulminant hepatic failure, and in fact HAV is responsible for 0.35% of all fulminant liver failure cases[21].

HAV transmission generally occurs through ingesting contaminated food or water[24]. Water matrices could prove an important route of HAV transmission even in industrialized countries, despite the lower prevalence than in less industrialized countries and the availability of advanced water management systems in these industrialized countries[24].

Acute hepatitis A has a broad clinical spectrum, ranging from mild cases with no noticeable symptoms, to acute liver failure leading to mortality in particularly severe cases[20,25]. Generally, HAV infections are asymptomatic or have only mild symptoms, and the disease ordinarily has a benign course with a spontaneous resolution[26]. In many developing countries, a majority of the population experiences infections during early childhood, without significant symptoms[20]. In addition, typical cases of acute hepatitis can be complicated by intrahepatic and rarer extrahepatic manifestations[26]. It can also present as acute hepatitis during pregnancy, during which it remains self-limiting[5,12].

Polyvalent immunoglobulins derived from pooled blood donations can be used for post-exposure prophylaxis, as one aspect of public health management related to hepatitis A[27]. Significant advances in HAV treatment have been developed, with improvements due to vaccination[28]. Preventive vaccines for hepatitis A, that are established as being safe for pregnancy, are recommended for women who are at risk of infection[7]. The post-exposure prophylaxis for hepatitis A is a single dose of immunoglobulin; in the event that immunoglobulin G is unavailable, a vaccination can be administered[7]. In addition, breastfeeding is regarded as safe in mothers with hepatitis A[7]. Based on recent findings, newly designed flavonoid hybrids may show promise as lead compounds for a novel anti-HAV drug candidate[29].

In order to limit environmental HAV circulation, developing countries need more effective treatment strategies for water and wastewater[24]. Prevention and hygiene measures to make foodborne virus outbreaks less common should focus on food workers and site of food production[23]. Pivotal strategies, such as proper investigation, surveillance, and reports on foodborne viral illnesses, are necessary for the development of measures to identify the presence and pathogenesis of viral infections with greater accuracy[23].

HBV

HBV is a virus based on deoxyribonucleic acid (DNA), and a member of the Hepadnaviridae family, which comprises ten genotypes (A-J); the virus can cause liver disease and increased HCC risk in those infected, as it replicates within the hepatocytes and interacts with several cellular proteins[30-32]. It constitutes a quiet public health threat worldwide[31]. More specifically, ageing with a chronic HBV infection is becoming an emerging public health priority[33]. In addition, people in prison run a greater risk of preventable mortality from HBV and other diseases, compared to the greater community as a whole[34]. Furthermore, the high prevalence of HIV infections amplifies replication of HBV, predisposes patients to chronicity, and complicates infection management[35]. On the other hand, recipient and donor hepatitis B infections in renal transplants are no longer regarded as relative contraindications[36].

Chronic hepatitis B (CHB) viral infections present a major global health threat, in spite of vaccinations and antiviral treatments[37]. As obesity and metabolic syndrome have increased in prevalence in recent years, non-alcoholic fatty liver disease (NAFLD) has become more common in patients with CHB[37]. Both diseases have the potential to lead to liver fibrosis and even HCC; however, the risk of dual etiology and the outcome of CHB combined with NAFLD have yet to be fully elucidated[37]. In addition, individuals with CHB virus infections who are at substantial risk of HIV infections benefit from pre-exposure prophylaxis (PrEP) using antiviral therapy based on tenofovir[38]. On the other hand, peculiarities related to the course of pediatric CHB could present important medical and social problems in healthcare, despite the presence of modern treatment and prevention protocols[39]. Pathogenetic mechanisms of HBV infections’ development and progression, the existence of occult poorly diagnosed forms, the unfeasibility of complete elimination of the virus, and the specificity of the pediatric immune response pose scientific questions that have yet to be fully resolved[39].

HBV is a highly prevalent virus estimated to have infected approximately 300 million people globally, and HBV infections present major global public health issues associated with significant morbidity and mortality; despite the existence of an effective vaccine, HBV remains the world’s seventh leading cause of mortality[35,40-44]. Due to worldwide population aging, HBV infections will become increasingly prevalent in elderly populations[41]. Furthermore, there has also been an increased worldwide prevalence of metabolic dysfunction-associated fatty liver disease, both among the general population and among CHB patients[45]. On the other hand, HBV is still the leading HCC risk factor, with a slight decline seen in most Asian countries, which has been attributed largely to HBV vaccinations of newborns, and chronic hepatitis treatment[46]. Approximately 7% of people living with HIV experience HBV infections, though there is substantial regional variation, and a greater prevalence among users of intravenous drugs[47]. HBV diagnoses increased from 2% to 14% between 2015 and 2019, but initiation of treatment increased from less than 1% to only 2%[48].

One unfortunate recent trend has been the 2019 novel coronavirus disease (COVID-19) pandemic and its interruption of the overall trend towards the eradication of HBV[49]. During the COVID-19 pandemic, many chronic HBV carriers living in rural areas lost access to healthcare facilities for screening, diagnosis, clinical management, and nucleo(t)side analogue therapy, mainly due to worries about becoming infected with COVID-19, restrictions on movement, and reduced income due to loss of employment[49].

Early stages of HBV infection general involve hepatic inflammation[50]. A type of cellular stress called endoplasmic reticulum (ER) stress always occurs when unfolded or misfolded proteins accumulate in the ER, exceeding the protein folding capacity[51]. Viral infections represent a risk factor for ER stress, due to the demand for post-HBV-infection rapid viral protein synthesis[51]. The hepatocyte is a cell with a large, well-developed ER, and hepatitis virus infections are widespread population-wide, suggesting that the interaction between hepatitis viruses and ER stress may have some significance for the management of liver diseases[51]. On the other hand, hepatic steatosis may suppress HBV viral activity, which could in turn lead to attenuated liver injury[45]. In contrast, diabetes mellitus, obesity, or other associated comorbidities could potentially increase the risk of adverse liver outcomes[45]. These findings suggest that the components of metabolic dysfunction-associated fatty liver disease could potentially have diverse effects on CHB’s clinical manifestations[45].

Hepatitis caused by HBV reactivation, while preventable, can also prove serious and potentially fatal[52]. HBV reactivation has most commonly been reported in patients experiencing strong immunosuppressive effects such as chemotherapy, especially patients undergoing rituximab-containing therapy for hematological malignancies, and stem cell transplant patients[52,53]. For patients with inactive and even resolved HBV infection, HBV genomes still persist in the liver[52]. The immune system controls the expression of these silent genomes[52]. When immune cells, most importantly B cells, are suppressed or ablated, this can lead to a seemingly resolved HBV infection being reactivated[52]. A low titer of hepatitis B surface antibody (HBsAb), or lack of HBsAb entirely, is a risk factor for HBV reactivation[53]. However, HBV reactivation cannot be predicted by HBsAb titers at baseline, or by changes over time[53]. Therefore, clinicians should bear in mind that every immunosuppressive therapy brings with it a risk of reactivation, irrespective of its mode of action[53].

Serologic testing is beneficial for diagnosis with molecular testing as indicated to guide hepatitis B management[7]. The primary roles of markers include HCC risk prediction, partial cure risk stratification cure (defined as off-therapy virological control), and functional cure [defined as HBs antigen (HBsAg) seroclearance plus undetectable serum HBV DNA for at least 6 months, which are associated with improved clinical outcomes][43,54]. Viral translational products, such as hepatitis e antigen, quantitative HBsAg, and hepatitis B core-related (HBcr) Ag, can be reduced through treatment that includes nucleos(t)ide analogues (NAs) and pegylated interferon α (peg-IFNα)[54]. These are valuable for defining the disease phase, delineating the endpoints of treatment, and predicting clinical outcomes, including risk of HCC and partial/functional cure[54]. At present, biomarker-based HBV infection detection systems are highly polarized[55]. One is a measurement system that is both fully automated and very sensitive, while the other is a simple system intended for point-of-care testing in areas with limited resources[55]. Recently, a fully automated, novel high-sensitivity HBcrAg assay (iTACT-HBcrAg, cut-off value: 2.1 LogIU/mL) has been developed[55]. It reflects intrahepatic covalently closed circular DNA, as well as serum HBV DNA[55]. This could make it useful as an alternative to HBV DNA for monitoring HBV reactivation and predicting the occurrence of HCC[55]. Even in patients who have undetectable serum HBV DNA or HBsAg loss, HBcrAg could potentially remain detectable[55]. Lower HBcrAg levels are associated with decreased occurrence of HCC in CHB[55]. Therefore, monitoring HBcrAg may prove suitable for determining therapeutic effectiveness, both for approved drugs and for novel drugs currently in development[55]. At present, the international guideline recommendation is anti-HBV prophylaxis for pregnant women who have high viral loads, in order to prevent mother-to-child transmission of HBV[55]. However, the vast majority (> 95%) of individuals infected with HBV live in countries without access to HBV DNA quantification[55]. Consequently, a rapid, easy HBcrAg assay would prove valuable as a point-of-care test[55]. Unfortunately, due to the lack of effect on covalently closed circular DNA, the template of viral transcription, and genome replication, this end point is rarely achieved through the current therapy[43]. At the same time, diagnosis remains below 10% worldwide, in spite of the existence of inexpensive laboratory tests for diagnosis and management, established decades ago[56]. Novel assays that provide more flexible approaches to determining patient health status have been developed with the goal of improving linkage to care[56].

At present, HBV infection management relies on constant and appropriate monitoring of viral activity, the progression of the disease, and the treatment response[57]. Quantitation of HBV core Ab (qAnti-HBc) can serve as a new non-invasive biomarker, which can help address multiple diagnostic issues[57]. It has been demonstrated to have meaningful correlations with phases of infection, the level of hepatic inflammation and fibrosis, exacerbation during chronic infections, and the presence of occult infections[57]. Further, qAnti-HBc levels have been recognized as being predictive of spontaneous or therapy-induced seroclearance of hepatitis B e-Ag (HBeAg) and HBsAg, relapse after therapy cessation, re-infection after LT, and viral reactivation upon immunosuppression[57]. However, qAnti-HBc should not be treated as a single “one size fits all” diagnostic test, and significant improvements to its diagnostic and prognostic value can be achieved by combining it with other diagnostic biomarkers like HBV DNA, HBeAg, quantitative HBsAg, and HBsAb[57]. Additionally, commercial qAnti-HBc diagnostic kits still need improved availability[57].

Early hepatic fibrosis diagnosis is a critical part of controlling the disease’s progression and decreasing the burden of end-stage liver cancer[50]. Fibrosis staging, through the current gold standard of liver biopsy, leads to improved patient outcomes, but brings with it an invasive clinical procedure, with post-procedural complications that can be unpleasant[50]. Routine blood test markers have promise as a diagnostic, for a biopsy-free means of early liver disease detection[50]. Many candidate routine blood test markers that have gone through phases of biomarker validation show much promise, but at present, their limitations include issues like predictive ability being restricted to only a few stages of fibrosis[50].

New viral biomarkers (HBV RNA, hepatitis B core Ag, small, middle, large HBs isoforms) are currently making their way through validation steps in clinical studies, while immunological biomarkers effectively do not exist outside of clinical assays for Abs to HBs, HBc, and HBe[58].

To control the progression of disease and decrease end-stage liver cancer burden, timely clinical management is vital[30,50]. Crucially, properly providing HBV birth-dose vaccinations, treating of chronic viral hepatitis, and providing harm reduction services makes risk factors both preventable and manageable[59]. In addition, HBV reactivation episodes are generally preventable, and the majority of HBV reactivation cases are manageable[60,61]. Furthermore, HCC can be detected, and with the appropriate training of medical personnel, curative management is possible if it is detected at an early stage, even in countries with limited resources, suggesting the need for effective screening and surveillance programs with recall policies[59]. Knowledge of the complete patient HBV serostatus is a key factor when deciding whether to pursue treatment, prophylaxis, or a pre-emptive approach[62]. Guidelines published in recent years encourage treatment with high barrier molecules in all chronic HBV patients, but long-lasting prophylaxis for patients who have inactive or resolved infections[62]. To date, there remain no drugs capable of curing hepatitis B beyond viral suppression; however, antiviral drugs targeting HBV (immunomodulatory therapies and gene silencing technologies) show promise as new approaches to hopefully eradicate this virus[28].

Currently available treatments are rarely able to cure CHB[63]. On the other hand, there has been remarkable progress in identifying new CHB treatment targets, being developed in the hopes of functionally curing patients who otherwise would need NA treatment for the rest of their lives[58]. Many of these new investigational therapies either target the immune system directly, or show promise in indirect impacts to immunity by modulating the viral lifecycle and Ag production[58].

The therapy available today is effective for viral suppression, but only on-treatment, and not off-treatment[43]. Guidelines currently recommend HBV screenings for any patients expected to undergo immunosuppressive therapy[64]. Following this, prophylactic antiviral therapy is to be administered to patients who test positive for HBsAg[52]. For patients who have resolved HBV infections, there are two main approaches[52]. The first of these is preemptive therapy guided by serial HBV DNA monitoring, and immediate antiviral therapy treatment once the HBV DNA can be detected[52]. The second approach is prophylactic antiviral therapy, particularly for patients who are undergoing high-risk therapies, especially anti-cluster of differentiation 20 monoclonal Ab or hematopoietic stem cell transplants[52]. The antivirals of choice are entecavir and tenofovir[52]. Though evidence is limited when it comes to guiding the optimal preventive measures, antiviral prophylaxis is recommended for HBsAg-positive patients who are undergoing novel treatments, including bruton tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and chimeric antigen receptor-T cell therapy[52].

Though NAs are commonly used as HBV infection treatments, they cannot hope to eradicate the virus, and the duration of treatment can prove to be lifelong if the endpoint for it is set at HBsAg seroclearance[65]. One proposed alternative is finite NA therapy without the requirement of HBsAg seroclearance, to allow patients with sustained undetectable HBV viremia for two to three years to cease treatment[65]. Unfortunately, NA withdrawal is almost inevitably followed by the reactivation of viral replication[65]. HBV reactivation might facilitate HBsAg seroclearance in some patients, but it could also cause serious acute flare-ups among a certain percentage of patients[65]. There are various factors surrounding the host, virus, and treatment that can complicate the occurrence and consequences of NA withdrawal flare-ups[65]. To ensure patient safety, it is crucial to accurately predict risks for severe flare-ups following cessation of NA[65]. On the other hand, NA therapy leads to low rates of recurrence and excellent outcomes after LT, both with and without hepatitis B immunoglobulin[13,66]. Given that tenofovir, which is one NA, is a potent inhibitor of HBV, providing PrEP to HBV patients is effectively tantamount to treatment of the HBV infection[38]. However, unknown risks of HBV reactivation, hepatitis, and acute liver failure during periods of antiviral cessation can cause some clinicians to be reluctant to initiate PrEP in chronic HBV patients[38]. Emerging data on antiviral cessation’s risks and benefits in chronic HBV patients suggest that it is safe to initiate PrEP, regardless of risks associated with non-adherence or discontinuation[38]. CHB patients who stop PrEP should be closely monitored for reactivation of HBV and flare-ups of hepatitis after ceasing administration of antiviral drugs[38].

HBV reactivation risk assessments are based on patient serological status and the immunosuppressive drug regimen planned[64]. For patients considered low-risk for HBV reactivation, management is a matter of serological monitoring for HBV reactivation, and, in the event of HBV reactivation, immediate preemptive antiviral therapy[64]. For patients considered intermediate- or high-risk for HBV reactivation, antiviral prophylaxis is to be initiated alongside immunosuppressive therapy, continuing for up to 18 months following termination of the immunosuppressive regimen[64,67]. Patients with past HBV infections run less of a risk of HBV reactivation compared to patients with chronic HBV infections, and antiviral prophylaxis could be initiated or patients could be monitored with the intent to initiate antiviral therapy on demand[67]. Patient management can also be improved through screening and management programs, and decision support tools based on these guidelines[64].

HBV-associated kidney disease (polyarteritis nodosa or membranous nephropathy) may necessitate immunosuppression when there is evidence of severe immune-mediated injury, weighed against potential viral activation risks[68]. Most HBV antiviral agents require dose adjustments for chronic kidney disease (CKD) patients, or end-stage kidney disease patients who need dialysis, and drug-drug interactions must be carefully evaluated in kidney transplant patients[68]. On the other hand, dental management in active hepatitis B consists of stabilizing patients until their active liver infections subside, with any dental treatment to be deferred until after recovery[69].

HBV transmissions can be prevented through vaccination; significant advances in HBV treatment have developed, and vaccination rates have improved[2,28]. There are effective universal vaccination programs, but they generally focus on younger populations, leaving the elderly population at a continued risk of a greater disease burden[41]. On the other hand, hepatitis B is the most prevalent form of the virus, and it is one of the targets of the ante-natal screening program[5,7]. Preventive vaccines for hepatitis B, for which pregnancy-safety has been established, are recommended for women who are at risk of infection[7]. In pregnant women who have active hepatitis B and an elevated viral load (> 200000 IU/mL) during the third trimester, antiviral tenofovir disoproxil fumarate treatment is recommended as prophylaxis against vertical transmission[5,7]. Neonates exposed to hepatitis B at birth should be given immunoglobulin G and a monovalent birth dose vaccine within 12 h, followed by a complete three-dosage vaccine series[5,7]. According to a report published by the WHO Eastern Mediterranean Region, regional hepatitis B vaccination coverage for infants was 82% for the third dose and 33% for the timely birth dose, as of 2019[48].

CHB can lead progressively to cirrhosis of the liver, an independent HCC risk factor[30,32]. Unlike in Western countries, chronic HBV infection is the main HCC etiology in many Asian countries other than Japan[70]. Recent, there has been mounting evidence pointing to the increasing importance of RNA methylation (m6A modification) in viral replication, immune escape, and carcinogenesis[32]. For patients with past HBV exposure who are undergoing immunosuppressive therapy, HBV reactivation represents a complication that could potentially prove fatal[64]. It can occur both in patients with chronic HBV infections, and in patients who have resolved HBV infections[64].

The available data provide evidence that, as a result of both direct and indirect mechanisms that promote hepatocarcinogenesis, HBV infection is associated with risks of developing HCC, with or without underlying cirrhosis of the liver[30]. There has been extensive continuous study of HBV-HCC’s molecular profile; it is known to be the result of altered molecular pathways, modifying the microenvironment and causing damage to the DNA[30]. HBV produces HBx, a protein that plays a key role in the oncogenetic process[30]. Furthermore, despite the obligatory dependence of HDV on HBV, HBV-HCC’s molecular profile has recently been discerned from that of HDV-HCC[30].

HBV is a common infection among HIV-positive people, due to the shared viral transmission methods[71]. Compared to individuals who have only HBV infections, people coinfected with both HIV and HBV experience accelerated liver disease progression, and face increased risks of HCC, liver-related mortality, and all-cause mortality[71]. Therefore, it is crucial for people with HIV to undergo HBV screenings and appropriate treatment[71]. On the other hand, acute HBV flare-ups following the start of antiretroviral HIV therapy have been reported in 20%-25% of coinfected cases, of whom only 1%-5% go on to develop clinical hepatitis[72]. This serves to underscore the significance of early recognition and management of immune reconstitution inflammatory syndrome-HBV flares, after antiretroviral therapy is initiated in coinfected patients[72]. In addition to this, antiretroviral therapy should continue to be administered, directed against both viruses[72].

HBV can lead to serious hepatic diseases, including cirrhosis, fulminant hepatitis, and HCC, and is a significant cause of mortality worldwide[2,40,43]. In addition, early studies on the natural history of HIV/HBV coinfection have shown that CHB progresses more rapidly in coinfected patients than in HBV-monoinfected patients, leading to HCC and other end-stage liver disease complications[47]. Furthermore, cancer patients with HBV infections face a high viral reactivation risk following cancer treatment[73]. On the other hand, there have been reports of good clinical outcomes following transplants from HBV-infected donors, because of the effectiveness and high tolerance levels of the treatments[66]. In summary, antiviral drugs can control the burden of advanced liver disease due to HBV, but short-term eradication remains unfeasible[74,75].

HCV

HCV is the sole member of the genus Hepacivirus within the Flaviviridae family, encoding a single-stranded positive-sense RNA genome that translates into a single large polypeptide, which is then proteolytically processed to yield the individual viral proteins, all of which are crucial for optimal infection by the virus[76]. HCV infection is a global health problem that can result in cirrhosis, HCC, or even death[2,59,77]. Hepatitis C infections are transmitted through blood[7]. It is often found as a chronic infection, in both the pregnant and non-pregnant populations[5,12]. Pregnant women can transmit HCV to the infant in utero or during the peripartum period; infection during pregnancy is associated with increased adverse fetal outcome risks, including restricted fetal growth and low birth weights[78]. In endemic areas, HCV/HBV coinfections are common, and coinfected patients run a greater risk of developing HCC, liver fibrosis, cirrhosis, and other liver diseases[79].

At the start of 2020, the estimated number of HCV infections worldwide was 56.8 million: A reduction compared to 2015[80]. Epidemiological data from the United States shows an increasing prevalence of hepatitis C in women of reproductive age; it is estimated that 1%-4% of pregnant women are infected with HCV, which in turn presents a transmission risk from mother to infant of approximately 5%[7,78]. In addition, chronic hepatitis C (CHC) is believed to affect some 2.4 million people[76]. However, HCV infections are 3- to 20-fold more prevalent among patients with severe mental illnesses, such as major depressive disorder, personality disorder, bipolar disorder, or schizophrenia, compared to populations without these illnesses[77]. It is also well established that HCV infections are disproportionately more common among prisoners than among the general population[81].

HCV remains prevalent among users of intravenous drugs, and transmission is generally associated with risk behaviors of injection[82]. Therefore, it appears to be prevalent among some blood donor populations, with high rates of HCV coinfection[5]. It has high rates of mother-to-child-transmission, but because it causes minimal or even no illness in infected infants, there is no need for antenatal screening[5].

Type-I IFN and other forms of cellular innate immunity will thwart the replication of viruses and other pathogens, forming the basis for use of conjugated IFNα in CHC management[76]. HCV suppresses this form of immunity as a countermeasure, through the enlistment of various gene products such as HCV protease(s), the main role of which is processing the large viral polyprotein into individual proteins with specific functions[76].

In HCV/HBV coinfections, HCV predominates, and suppresses replication of HBV[79]. The HCV core proteins and the IFN activated by HCV serve to suppress HBV[79]. Immunosuppression has also been observed in patients coinfected with HCV and HBV[79]. Decreased HCV-neutralizing antibody response and circulation of Th1-like T follicular helper cells is seen in patients coinfected with HCV and HBV[79].

Serologic testing can assist with diagnoses, using molecular testing as indicated in order to guide hepatitis management C[7]. However, due to insidious progression and the lack of any significant early-stage clinical symptoms, CHC is often diagnosed only after cirrhosis and HCC develop[83].

Progress toward curing HCV has been slow ever since it was discovered in 1989, and treatment options were previously based on peg-IFNα, which is associated with adverse events of a neuropsychiatric nature; consequently, this led patients with severe mental illness to be excluded from HCV treatment, elimination programs, and clinical trials[77,84]. However, there have been significant advances in HCV treatment, including the advent of curative therapies[28,84,85]. Since 2014, the approval of safe, well-tolerated oral direct-acting antiviral (DAA) agents has led to a paradigm shift in the treatment of HCV infections, and these DAAs can even eradicate HCV infections. For the first-choice HCV therapy, recent guidelines recommend pan-genotypic drugs (i.e., drugs effective across all HCV genotypes)[2,77,85-89]. DAA regimens promise cured HCV with 8-12 wk of a well-tolerated, once-daily therapy[88]. The high effectiveness and low drug resistance of DAAs have made a CHC cure possible, leading the WHO to propose a program for the global elimination of viral hepatitis[83,90]. Numerous countries have adopted initiatives to eliminate HCV, to the extent that the elimination of HCV is now a matter of healthcare delivery[85,90]. DAA therapy for post-LT recurrent hepatitis C infections is associated with a sustained virological response (SVR) of nearly 100%, regardless of genotype[13]. In addition, this therapy is feasible for patients who have CKD or end-stage kidney disease requiring dialysis, and has high cure rates with no need for dose adjustments[68,87,89]. DAA therapy alone can treat HCV-associated cryoglobulinemic glomerulonephritis, while concurrent antiviral and immunosuppressive therapy is necessary in cases involving severe, organ-threatening manifestations of cryoglobulinemia[68]. On the other hand, despite the high rate of successful HCV eradication, the risk of liver-related events remains even after the HCV cure, such as HCC, which is the major complication of HCV infections; patients at risk of HCC should be placed under continuous HCC surveillance[89]. DAA agents have been safely administered in hematological settings[62]. They should be considered for use as a first-line single treatment in indolent lymphomas, combined with chemotherapy in aggressive cases[62]. Treating active pediatric HCV infections (HCV-RNA positive) is now simple and straightforward, as various DAA regimens have been approved for children above three years of age[91]. Screening for hepatitis C during pregnancy, and the subsequent management thereof, remains an unsettled matter, but the introduction of DAA drugs could be revolutionary if their safety during pregnancy can be established[5,7]. Breastfeeding is also regarded as safe for women with hepatitis C[7].

Regarding DAA regimens, real-life studies suggest that the SVR of sofosbuvir (SOF)/daclatasvir (DCV) is acceptable, and that these can be used for the successful management of HCV[92]. Nonetheless, utilization of SOF/DCV has been limited by the longer duration of treatment in genotype-3 patients, as well as the need for ribavirin (RBV) in treatment-experienced patients, which leads to greater odds of adverse effects[92]. DCV is likely to remain in therapeutic use as an option for resource-limited-setting management of genotype-1, genotype-2, and genotype-4 patients, while genotype-3 patients are more likely to benefit from RBV-free DAA combinations such as a 12-wk regimen of velpatasvir (VEL)/SOF, or an 8-wk regimen of glecaprevir/pibrentasvir (GLE/PIB)[92]. In 98% of patients, GLE/PIB, VEL/SOF, and other DAA combination therapies have been found to succeed in eradicating the virus, even in cases where previous treatments had failed or where there are resistance-associated substitutions[84,92,93]. There is currently debate focusing on hepatitis C, and expectations for use of the newly approved HCV pan-genotypic once-daily oral DAAs, GLE/PIB, and SOF/VEL/voxilaprevir[93]. On the other hand, management of difficult-to-cure HCV patients has included individuals who had failed prior DAAs, intravenous drug users, and patients with decompensated cirrhosis or renal insufficiency[93].

Adverse events during DAA treatment are rare or mild, and patients who have comorbidities such as compensated cirrhosis are generally eligible for treatment[84]. However, even after retreatment, a small percentage of patients fail to eradicate the virus[84]. This failure is usually mainly due to NS5A P32 deletion mutants emerging after initial DAA therapy in genotype-1b patients, though the reason for failure remains unknown for some patients[84]. In these patients, alternative therapies such as SOF plus RBV, that do not rely on NS5A inhibitors, can be attempted[84]. Scaled-up treatment efforts present a challenge, and part of the issue is that many viral carriers are simply not aware that they are infected[84]. This can result in irreversible long-term liver damage, and if patients are not diagnosed in time, they could go on to develop HCC or liver failure even after the virus is eliminated[84]. DAA therapy is partially offset by the increasing abuse of intravenous drugs[75]. On the other hand, DAA therapy must be personalized for decompensated patients, with consideration given to current and proposed guidelines of associations such as the European Association for the Study of the Liver, or the American Association for the Study of Liver Diseases[94].

In HCV/HBV coinfections, both viruses interact in the liver; treating these coinfections is genotype-based and complex, due to interactions between the viruses[79]. Treatment of HCV-dominant cases uses DAA drugs and peg-IFN plus RBV, with continuous monitoring of aspartate aminotransferase (AST) and alanine aminotransferase (ALT)[79]. Treatment of the less-common HBV-dominant cases uses peg-IFN and NUC, with monitoring of AST and ALT[79]. The SVR rate in HCV/HBV coinfections is higher than for monoinfections when treated with DAA drugs, but there is a risk that HBV could reactivate during or after therapy[79]. Reactivation is less common in patients treated with DAA drugs than in patients treated with peg-IFN plus RBV[79]. HBcrAg, HBV DNA, HBV pregenomic RNA, and other HBV biomarkers are not effective for predicting HBV reactivation; only the HBsAg titer serves as an effective biomarker for HBV reactivation[79]. HCV can also be reactive, but has only been seen in very rare instances in which HBV was present and treated first[79]. In addition, much like HBV, HCV-infected cancer patients run a high risk of viral reactivation following cancer treatment[73]. However, there remains very little data regarding HCV reactivation in cancer patients who have been treated with immune checkpoint inhibitors and other newer anticancer drugs[73].

As of this writing, a CHC vaccine remains under study[83]. Therefore, minimizing sources of infections is an important step toward eliminating CHC beyond cutting off transmission routes, which would require the screening, diagnosis, and treatment of as much of the population as possible[83]. Hospital-based screening strategies have proven cost-effective in CHC screening management, as reported both domestically and internationally[83]. In addition, LT is the only ultimate solution warranted for HCV-induced decompensated cirrhosis[94]. On the other hand, for CKD patients, HCV infections have adverse liver, kidney, and cardiovascular consequences, including for patients undergoing dialysis therapy or who have kidney transplants[95].

HDV

HDV, or hepatitis delta virus, is the smallest virus able to causing disease in humans[96]. HDV was discovered in 1977 and represents a significant cause of mortality worldwide; it is the most severe form of chronic hepatitis, with rapid development of cirrhosis, hepatic failure, and HCC[40,97-100]. HDV infections in humans require establishment of hepatitis B, with infection replication and propagation relying on HBsAg and host cellular machinery[40,96,99-101].

Hepatitis D is generally encountered as a chronic infection in both the pregnant and non-pregnant populations[5,12]. The distinctive clinical characteristic of chronic hepatitis D (CHD) in endemic countries, observed in Europe in the 1980s, are accelerated progression to cirrhosis and HCC[102].

Compared to chronic HBV monoinfections, HDV accelerates liver fibrosis, increases HCC risk, and increases the pace of hepatic decompensation[99]. Therefore, coinfection with both HBV and HDV often results in increased disease severity compared to HBV on its own, with greater likelihoods of cirrhosis, liver failure, and HCC[40,96]. In addition, there are distinct clinical courses for hepatitis D coinfections and superinfections; the latter is more likely to result in chronic infection[11]. On the other hand, HDV infections have been found to increase hepatic decompensation risk and HCC risk among patients who are coinfected with HIV and HBV[103].

HDV is highly prevalent, infecting an estimated 12-72 million people worldwide[40]. In addition, chronic HDV infections affect approximately 12 million people worldwide[101]. However, there is only limited data regarding the prevalence, determinants, and outcomes of HDV infections for people who are coinfected with HIV and HBV[103].

The recommendation from the Chronic Liver Disease Foundation is that all HBsAg-positive patients should be screened for HDC[99]. Initial screenings should use an assay to detect Ab generated against HDV, and patients who test positive for anti-HDV immunoglobulin G Ab should then undergo quantitative testing for HDV RNA[99]. At present, the gold standard for staging of this rapidly progressive and particularly severe variety of CHD remains a liver biopsy[100]. On the other hand, there remains an unmet need for clinical CHD infection monitoring for managing progressive disease, as a result of which there is ongoing investigation into the utility of non-invasive fibrosis markers in hepatitis D[100].

Despite recent progress in this realm, the treatment options that are currently approved remain very limited, in terms of both availability and efficacy; some patients are non-responders to these existing therapies, and in most cases, currently available drugs are unable to cure HDV[96,101,102]. As a result, HDV management presents a challenge for physicians, alongside the urgent necessity of new drugs development[96,101].

HDV still tends to be underdiagnosed, with no standardized management having been developed to date[97]. Though alternative treatments have been developed, peg-IFNα seems likely to continue playing an important role in hepatitis D management, either on its own or in combination[104]. Peg-IFNα has been available for 30 years now, and is recommended by guidelines, though not approved, with low efficacy and poor tolerability; the result is sustained virologic response in no more than 25% of patients[98,101,103-105].

Among the new treatment strategies currently being clinically evaluated, the entry inhibitor bulevirtide (BLV) is the only one thus far to have received conditional European Medicines Agency approval. Approval was granted in July 2020, for a 2 mg daily dose to treat adult patients with compensated CHD[105]. BLV has successfully been used as a long-term monotherapy to treat advanced compensated cirrhosis patients[105]. Until new anti-HBV and anti-HDV drugs eventually become available for combination studies, BLV treatment remains the only available anti-HDV therapeutic option that could improve long-term prognoses in difficult-to-manage CHD patients[105].

Liver decompensation, HCC, and other complications can impact the survival of HBV patients, and concurrent HDV infections lead to worse courses of disease[30]. The hepatitis D disease burden appears roughly 10-20 years after infection[9]. The most severe form of viral hepatitis is CHD, which is characterized by causing the largest risk increases for cirrhosis and HCC[101,105]. To date, there is only limited data regarding HDV’s epidemiology, natural history, and treatment for patients coinfected with HIV and HBV[103]. There is still a need for further research to fill in knowledge gaps, for improved management of HDV coinfections in cases involving HIV/HBV coinfections[28].

HEV

HEV, the causative agent of hepatitis E, is a single-stranded, positive-sense RNA virus[106,107]. This virus is part of the genus Orthohepevirus in the family Hepeviridae, which has four major genotypes considered closely human-related[106,108]. Genotypes 1 and 2 of HEV exclusively infect humans, through fecal-oral transmission, leading to acute, self-limited hepatitis[107,109]. Genotypes 3 and 4 are harbored in a broad variety of animal species around the world, and can be transmitted zoonotically to humans by means of fecal matter, direct contact, or ingestion of contaminated meat products; these genotypes primarily affect immunosuppressed populations, leading to chronic HEV infections[106,107,109-112]. HEV infection has distinct features, but these vary by both genotype and geographical region[110]. Today, it is considered a threat to worldwide health, in developing and industrialized countries alike[113]. Studies have increasingly noted that HEV could be classified as a re-emerging virus in developed countries, and that tracking incident case numbers (i.e., number of new acute infections) would be valuable for public health[9,114,115]. HEV generally affects younger populations and is self-limiting, but it can also develop into severe illness, particularly among adults and pregnant women, or as a chronic infection in immunocompromised patients, especially recipients of solid organ transplants[9,109-111,113,115-117]. Epidemics caused specifically by genotype 1 of HEV (but not any other genotype of Orthohepevirus A) demonstrate an adverse relationship with pregnancy in humans[108]. At present, this association’s complex pathogenesis is not well understood[108]. It is conceivable that there are multiple factors at play in the severe liver disease experienced by pregnant women, including infection and damage to the maternal-fetal interface caused by HEV genotype 1, severe fetal/neonatal hepatitis caused by vertical transmission of HEV to the fetus, and viral replication promoted by a diverse combination of viral and hormone-related immune dysfunctions in pregnant women[108].

Despite WHO estimates suggesting annual HEV infection numbers around 20 million people, its epidemiology remains unclear[109]. The disease is associated with higher prevalence, and lower morbidity and mortality[5,110,111,113,117]. However, infections can be severe in pregnant women: it is associated mortality of as much as 30% during the third trimester, with special attention needed in endemic areas[5,113].

HEV is mainly transmitted by means of the fecal-oral route (ingestion of tainted water or food), through contact with infected animals and/or raw meat products from these animals, and through blood transfusions[5,7,11,107,113,115]. Some animals are natural HEV reservoirs, including pigs, wild boars, sheep, goats, rabbits, camels, and rats; as a result, people who come into close contact with these animals face an increased risk of contracting HEV[115]. Until fairly recently, HEV was regarded as being the main cause of acute hepatitis epidemics in developing regions, due to drinking water supplies being contaminated with human fecal matter[112,114]. However, there has been a paradigm shift in the past several years in the general understanding of HEV’s epidemiology and clinical features[118]. In the past, HEV was described as an acute form of hepatitis associated with waterborne outbreaks in areas with poor sanitation, but today, it is known to be endemic even in certain industrialized areas, including some regions of Europe, and is considered likely to be zoonotic in origin[112,118].

Initially, HEV was believed to exclusively lead to acute hepatitis[25,115]. However, HEV infections can also cause chronic hepatitis, and even extrahepatic manifestations like neurological and renal diseases; in fact, it is the world’s most common cause of acute viral hepatitis[112]. The severity of the disease may also be affected by altered immune status, hormonal levels, and viral factors[113]. HEV infections during pregnancy are associated with high rates of preterm labor, as well as vertical transmission[113]. In 2000, an association was discovered between preceding HEV infection and Guillain-Barre syndrome (GBS), though HEV-associated GBS remains poorly understood[119]. In the Netherlands, 5% of GBS patients had a preceding acute HEV infection; in Bangladesh, where HEV is endemic, a higher rate of 11% was found[119]. The in-serum presence of antiganglioside GM1 or GM2 antibodies in some HEV-associated GBS patients would suggest that HEV infections could trigger GBS through the activation of an autoimmune response that mistakenly aims to destroy myelin or axon[119]. There is no obvious difference between management of HEV-associated and non-HEV-associated GBS[119].

To date, diagnosis and prevention continue to be difficult in various clinical settings[109]. At present, HEV infections are diagnosed through measurement of anti-HEV Ab, HEV RNA, or viral capsid Ag in blood or stool[112]. Preventative efforts are necessary as a key part of managing this disease, to reduce overall incidence of both acute and chronic hepatitis E, in both non-endemic and endemic countries[115]. Post-HEV-infection management is multidisciplinary, requiring close monitoring for development and management of acute liver failure[108]. There is still no completely defined optimal therapy for hepatitis E virus in transplantation[66]. Acute hepatitis E does not require any specific treatment, as it is generally self-limiting[112]. However, due to the existing risk of chronic HEV infections, immunocompromised patients should undergo serum HEV-RNA screenings in the event of any signs or symptoms that suggest[62]. In addition, management of immunocompromised individuals involves lowered immunosuppressive drug dosages, and/or treatment with RBV, an antiviral agent[62,112]. It remains the only specific treatment currently recommended for HEV infection, as it is efficient in most, though not all cases[120].

Management of HEV-associated GBS consists largely of supportive therapy and immunotherapy[119]. Most reported cases used intravenous immunoglobulin or plasma exchange, which is the main clinical treatment strategy for HEV-associated GBS[119]. However, a key question in need of further investigation is whether antiviral therapy could serve as an additional strategy beyond the routine therapy, to help reduce the course of disease[119]. The expert commentary for HEV genotype-1 or genotype-2 infections during pregnancy is to administer mainly supportive treatment, with diligent monitoring and intensive care[110]. The literature available does not endorse therapeutic termination of pregnancy[110]. Early LT should be considered a possibility for these patients, though LT indications and timing remain controversial[110]. Significant advances in HEV treatment have been developed, and vaccination rates have improved[28]. There is a recombinant HEV vaccine, but as of this writing only China and Pakistan have approved it for use and commercial availability[5,112,115]. On the other hand, there is currently no established treatment available for HEV in pregnant women[12,113].

Regarding prognosis, chronic HEV infections can exist and rapidly progress to liver fibrosis, liver cirrhosis, and decompensation in immunosuppressed patients, including recipients of solid organ transplants[111,117]. In addition, genotype-1 or genotype-2 HEV infections during pregnancy, especially during the third trimester, can develop into severe illness and fulminant liver failure; likewise, there have been reports of poor outcomes for both mothers and fetuses[110].

MAJOR INNOVATIONS

There have been several major innovations related to this topic brought about by recent research. First, clinicopathological studies have demonstrated that HAV is primarily the cause of acute infections, and this is, to a certain extent, associated with HCC[121]. Regarding HBV, activation of the Stat3 gene is an essential component in mice models for the onset of hepatic inflammation, and in chronic carriers of HBV, it serves as a novel early-stage immune activation indicator[122]. Additionally, HBV X protein gene mutations have a strong association with HCC incidence[121]. Consequently, one potential innovation for accelerating diagnostics and therapy could be mapping the microRNA (miRNA) responsive to HBV and HBV-specific proteins, including HBV X protein, to potentially aid against infections and associated diseases[123]. Transcription of HBV’s covalently closed circular DNA is subject to dual regulation, both by viral proteins and host factors[124]. This miRNA can regulate target genes’ expression at the post-transcriptional level, thus potentially playing a crucial role in these pathologies[123,124]. More specifically, miR-3188 is a key miRNA, which targets the host protein Bcl-2 to regulate transcription of HBV[124]. This realization provides further insight into how covalently closed circular DNA transcription is regulated, implying new anti-HBV treatment targets[124]. Another study found that the interferon pathway is regulated by the sterol regulatory element-binding protein cleavage-activating protein (SCAP), through the sterol regulatory element-binding protein, and that the HBV lifecycle is affected by this[125]. In addition, SCAP deficiency contributes to suppressing HBV by activating IFN and expressing IFN-stimulated genes within cells[125]. Therefore, given that SCAP involves regulating HBV infections, these results could prove valuable in the development of novel antiviral approaches to treating HBV[125]. For HCV, HCV core protein expression contributes to the accumulation of hepatocellular lipids, which in turn promotes tumorigenesis[121]. For HDV, the Janus kinase 1 gene may prove to be a key host factor for viral replication, as well as a potential new antiviral treatment target[126]. As for HEV, there were enhanced surveillance and molecular characterization studies performed in Japan from 2014 through 2021, revealing that 3a and 3b were the most prevalent genotypes[127]. In addition, there have been more and more chronic infections of late, particularly in patients who are immunocompromised and in patients who have received organ transplants, which could lead to increased risk of progressing to cirrhosis and onset of HCC[121]. Finally, successful implementation of telementorship across both high and low-to-middle-income countries could lead to improved provider knowledge and experience when it comes to managing viral hepatitis[128]. Telementorship presents a valuable opportunity to further expand upon existing experience, to provide support for non-specialist healthcare workers and to work toward eliminate viral hepatitis[128].

CONCLUSION

In 2016, the WHO released a plan to eliminate viral hepatitis as a public health threat by 2030, and existing gaps and prospects for both regional and worldwide eradication of viral hepatitis were discussed in light of the WHO roadmap to that point[94,123]. Today, patients can be sufficiently treated before the disease advances to a more progressed phase, but the biggest challenge remains linking patients to care and therapy. However, future therapies must be extremely safe, and ideally limit the required treatment period. In addition, a better understanding of the pathogenesis will help in developing potential treatment strategies targeting viral hepatitis infections.