Both in the context of morbidity and mortality, the global burden of viral hepatitis is substantial. Hepatitis A virus (HAV) and the hepatitis E virus (HEV) transmit infection via orofecal routes and usually induce self-limiting acute hepatitis or asymptomatic infection. Although both are sporadically present in different countries, there have also been endemic and epidemic outbreaks of these viruses. As per the statistics of the World Health Organization (WHO), the number of deaths per year due to HAV and HEV is, approximately, 44,000 and <10,000, respectively.[1,2]
Unlike HAV and HEV, hepatitis B virus (HBV) and hepatitis C virus (HCV) cause chronic infection. As of 2019, approximately 296 million people, WHO estimates, are chronically infected with HBV, and around 1.5 million new infections emerge each year. On top of this, in 2019, about 820, 000 deaths occurred as a consequence of HBV-related complications. On the other hand, about 58 million people are chronically infected by HCV, and each year, there are about 1.5 million new cases and nearly 290,000 deaths due to HCV-related liver diseases.
Considered together, all the hepatitis viruses remain a threat to the public health delivery system. However, improved public health measures around the world, especially the increased supply of safe water and decreased instances of unsafe feces disposal, and the development of vaccines for HAV and HEV, which are used in limited proportions, have enhanced the containment of HAV and HEV globally. Although there are no vaccines for HCV infection, the recent development of highly effective antiviral drugs has shown considerable promise in largely curing HCV infections. Thus, to help contain the HAV, HEV, and HCV to certain levels and ensure the achievability of the “Elimination of Hepatitis by 2030” plans, insights into these viruses are paramount.
However, despite the existence of highly potent prophylactic HBV-containing vaccines, the prevalence of several variables, such as the cellular and molecular mechanisms related to the acquisition of HBV infection, the pathogenesis of the HBV-induced liver diseases, and the limitation of antiviral drugs against chronic hepatitis B (CHB), have forced the “Elimination of Hepatitis by 2030” plan to prioritize the control and containment of HBV.
In our review of this extremely complex global plan, we aim to answer why, despite careful preparations and existing scientific developments, the plan could miss its intended time frame. Doing so, we are confident, could help re-evaluate the present working principles of the plan and craft new strategies to realize its goals.
Targets of “Elimination of Hepatitis by 2030” and the focal points
To attain the target of “Elimination of HBV and HCV by 2030”, WHO after the due consideration of various variables of 2015. The target mainly encloses two important aspects: (1) service coverage and (2) impact leading to elimination. Under the term “service coverage”, there are two main variables: prevention and treatment [Table 1]. The four spectra of prevention that have been emphasized include the following: (1) three doses of hepatitis B (HB) vaccine for infants, (2) prevention of mother-to-child transmission of HBV: HB birth dose vaccination or other approaches, (3) blood and injection safety, and (4) harm reduction. The most challenging part of elimination is treatment. If prevention and treatment can be properly ensured, there will be marked effects on the incidence and mortality of HBV infection, and the target of “Elimination of Hepatitis by 2030” can be achieved.
Table 1 -
Service coverage targets that would eliminate HBV and HCV as public health threats, 2015–2030
||(1) Three-dose hepatitis B vaccine for infants (coverage %)
||(2) Prevention of mother-to-child transmission of HBV: hepatitis B birth-dose vaccination or other approaches (coverage %)
||(3) Blood and injection safety (coverage %)
||Blood safety: donations screened with quality assurance
||Infection safety: use of engineered devices
||(4) Harm reduction (sterile syringe/needle set distributed per person per year for PWID)
||(5a) Diagnosis of HBV and HCV (coverage %)
||(5b) Treatment of HBV and HCV (coverage %)
||5 million (HBV) 3 million (HCV)
||80% eligible treated
|Impact leading to elimination
||Incidence of chronic HBV and HCV infections
||Mortality from chronic HBV and HCV infections
Prevention strategies for combating HBV
Out of the four strategies related to the prevention of the further spread of HBV infection, the administration of three doses of vaccines for infants seems to be an achievable goal. Most countries have adopted HB vaccination in their expanded program of immunization (EPI). Regarding the blocking of mother-to-child transmission, the prevailing vaccination program of three doses of HB vaccine seems optimal. Although the birth-dose vaccination within 24 hours of birth may be a better proposition for preventing HBV infection in children, a recent analysis unveiled its pros and cons: most, but not all, countries of South-East Region of WHO (SEARO) are advancing to attain the WHO goal of HB vaccination. Most importantly, the study found that the birth-dose vaccination may not be a major limiting factor in the implementation of vaccine-induced prevention of HBV transmission. Rather, due to structural limitations, birth-dose vaccination may not be appropriate for the containment of HBV infection in children. In addition, it may not be acceptable in many Asian and African countries that harbor the majority of HBV-infected individuals. Therefore, strengthening the ongoing EPI program should be highly emphasized. Out of the 11 countries of SEARO, four have attained the WHO target of less than 1% prevalence of HBV among children aged ≥5 years, and two of these countries have not implemented birth-dose vaccination in their HBV control program. Table 2 provides more detailed information on the four of the SEARO countries that have reached the HB vaccination goal.
Table 2 -
Kinetics of HBsAg seroprevalence in four countries that have met the WHO target of containing HBV in children
||HBsAg seroprevalence before vaccine introduction % (95% CI)
||HBsAg seroprevalence in children aged ≥5 years after vaccine introduction % (95% CI)
||Year of verification of <1.0% HBsAg seroprevalence
HBsAg: Hepatitis B surface antigen; WHO: World Health Organization; HBV: Hepatitis B virus; CI: Confidence interval; NR: Not reported.
To move forward with “Elimination of Hepatitis by 2030”, safe blood supply and harm reduction should also be implemented in all countries. However, most of the developing countries have been practicing only transfusion after checking for HB surface antigen (HBsAg). Since some HBsAg-negative persons may harbor the HBV DNA, these countries should practice more precise checking of the HBV DNA.
Treatment of CHB patients as part of “Elimination of Hepatitis by 2030”
The most pertinent part of the “Elimination of Hepatitis by 2030” plan depends on the treatment of CHB patients. They suffer from liver damages and are prone to developing cirrhosis of the liver (LC) and hepatocellular carcinoma (HCC), diseases regarded as intractable liver diseases and characterized by symptoms such as ascites, jaundice, bleeding of esophageal varices, and other liver cancer symptoms, all of which leave the patients with serious complications and compromise their quality of life.
In addition, treatment is also important from the public health point of view of attaining the goal of the “Elimination of Hepatitis by 2030” plan. Almost all CHB patients harbor HBV DNA and HBsAg. Unless these patients, the living and permanent reservoirs of HBV, are treated properly, the two main goals of the plan cannot be attained. To achieve by 2030 the target of reducing the incidence of chronic HBV infection to 90% and the mortality due to CHB to 65%, both compared to the levels of 2015, 80% of CHB patients should be treated.
The attainment of the treatment goal of “Elimination of Hepatitis by 2030” seems unrealistic
It seems that the reduction of the incidence of HBV and mortality due to HBV is not an achievable goal. In 2015, there were about 257 million chronic HBV-infected patients in the world and roughly 887,000 deaths.[7–9] According to the estimates of WHO, the number of CHB patients increased to 296 million in 2019. When the “Elimination of Hepatitis by 2030” plan was formulated, all the existing methods were assumed to decrease the number of CHB patients by 30%. However, this has not happened – there has, instead, been an increase from 257 million CHB patients to 296 million CHB patients, an increase of 39 million.
Why the target of reduction of CHB patients could not be met
Within 5 years of the implementation of “Elimination of Hepatitis by 2030”, the number of CHB patients increased. Thus, to ask how the target of reduction of CHB patients by 90% would be achieved by 2030 from their baseline of 2015 seems natural. Moreover, WHO has reported that there are 1.5 million new CHB patients each year.
Here, we discuss why the target of “Elimination of Hepatitis by 2030” would remain in jeopardy.
- A. The hallmark of any containment strategy is finding out the target population. Paradoxically, about 90% of CHB patients are not aware of their HBV infection. The WHO targets and guidelines have not suggested effective measures to find the millions of undetected CHB patients.
- B. CHB is a slowly progressing disease, usually remaining dormant for decades after infection with HBV. Only after some decades do symptoms appear, and in most cases, the patients develop complications.
- C. The major challenge is to discover the millions of undetected CHB patients who are unaware of their HBV infection. Developed and advanced countries have several means to detect HBV infections. They regularly check their general population for HBV and HCV, including those in the CHB at-risk group and pregnant women (for HBV). However, no such mechanisms exist in developing and resource-constrained countries, where most of the CHB patients reside. Though EPI programs and extensive vaccination drives could reduce new HBV infections in children, the existing 296 million CHB patients can infect healthy individuals. Thus, it seems plausible that HBV would be mostly eliminated from rich, developed, and advanced countries in the future, but little progress will be accomplished in developing countries.
The ongoing treatment strategy for CHB and its limitation in reducing CHB
For treating CHB patients, several drugs have been repurposed or developed, which can be mainly classified into two major groups: (1) Interferon (IFN) and its pegylated form, pegylated interferon (Peg-IFN) and (2) nucleoside analogs (NUC). IFNs have been used in CHB patients since the 1980s as injectable antiviral drugs, whereas oral NUCs have been used in CHB since the 1990s. Thus, about four decades have passed since initiating the drug treatment of CHB. Although these drugs have induced some benefits in some CHB patients, they have notable limitations, such as adverse effects, finite versus infinite treatment regimens, levels of efficacies, capacities to block progressive liver diseases such as LC, HCC, and costs.[10–13]
The present and future of “Elimination of Hepatitis by 2030”
The scope and limitation of the ongoing preventive and therapeutic strategies for the containment of HBV infection and attainment of the “Elimination of Hepatitis by 2030” plan have been critically analyzed.
Scientifically analyzing the overall strategies for the “Elimination of Hepatitis by 2030”, it becomes evident that there remains strong optimism regarding the reduction of new cases of HBV infection and attainment of preventive targets. The WHO should analyze the program development on a country-by-country basis in six regions of WHO, and technical support would be most important to attain the target. Moreover, the realistic targets should be emphasized based on the socio-economic and cultural basis of each country. Some strategies that might be applicable in developed countries could be irrelevant in many developing and resource-constrained countries of Asia and Africa. There remains a strong demand to improve the HBV-free transfusion of body fluids, and the checking of body fluids should move from only-HBsAg-checking to nucleic acid testing. The usage of safe needles and syringes has become a common practice in most developing countries, with some exceptions, and this could be addressed by the country with help from the international arena. Moreover, the target of harm reduction cannot be achieved only through the distribution of condoms; there is a strong necessity to educate society to achieve the target. Thus, a comprehensive effort of each country with international collaboration would form the basis of blocking new HBV infection in the global context.
How to find out the undetected CHB patients around the world?
Out of an estimated 296 million CHB patients (as of 2020), only 10% are aware of their infection. The rest millions of patients do not know that they are infected with HBV and could continue spreading HBV infection to healthy individuals, who, in turn, will also remain undetected. This is responsible for the increase of CHB patients from 257 million in 2015 to 296 million in 2019. Finding undetected patients is a highly complex task, and we need to proceed systematically. Some of the ways for doing so are as follows:
- 1. Establishing a strong surveillance system for tracing CHB patients.
- 2. Creating a strong campaign surrounding HBV infection through mass media to educate the general population.
- 3. Creating arrangements for checking HBV during mass screening at different levels: company, offices, schools, and hospitals.
- 4. Initiating HBsAg checks during entry to job and others in many countries that do not practice this.
- 5. Checking all members of HBV-positive households for HBsAg.
- 6. Making HBsAg checking free or cheaper to improve access for everyone.
- 7. Organizing the assessment kit of HBsAg by WHO and other bodies.
- 8. Researching to develop cheaper HBsAg kits.
Treatment of CHB patients with commercially available NUCs
As shown in Table 1, according to the “Elimination of Hepatitis by 2030”, less than 1% of CHB patients have been receiving some sort of treatment, and this should be increased to 80% by 2030.
But is it possible?
- 1. Several commercially available antiviral drugs can now be used to treat CHB patients. However, there are some limitations to these drugs in addition to their limited efficacy and notable adverse effects.[14–23]
- 2. All the antiviral drugs can reduce HBV DNA in the sera. Once patients who take antiviral drugs for 2 to 3 months experience HBV DNA negativity, they assume that they do not require further treatment. However, prolonged therapy with antiviral drugs is required to keep HBV DNA under control.
- 3. The cost of antiviral drugs is not bearable for the CHB patients of many countries.
- 4. Proper follow-ups cannot be accomplished for patients on antiviral drugs.
- 5. The adverse effects of antiviral drugs, especially when they are discontinued, cause havoc in patients’ lives.
These facts indicate that there should be a drug for CHB treatment that should be endowed with the following aspects:
- 1. Finite therapy
- 2. Safety
- 3. Efficacy
These factors strongly demand new and innovative drugs to be prepared based on the evidence of HBV pathogenesis.
Innovative therapy for CHB patients
The scope and limitations of the antiviral drugs involved in CHB treatment are becoming clear day by day. Moreover, several investigators have revealed their preclinical data and clinical observations about novel drugs for CHB patients. These include a large list of drugs:[24–30]
- 1. Entry inhibitor
- 2. Neutralizing antibodies
- 3. RNA interference (RNAi)
- 4. Core/capsid inhibitors
- 5. HBV cccDNA disrupters/silencers
- 6. Ribonuclease H (RNaseH) inhibitors
- 7. HBV translator inhibitors
- 8. Capsid assembly inhibitors
- 9. HBsAg release inhibitors
- 10. HBV immunomodulators
As HBV is a non-cytopathic virus and the liver damage and progression to fibrosis are mediated by immune responses, there is a good chance that immune therapy may be an effective therapeutic alternative to NUC. Immune therapy in CHB patients began since the 1980s, and it has undergone several alterations in approaches with regard to using different immune therapeutic agents.[31–59] However, there is no consensus on developing an immune therapy that is inclusive of the treatment recommendations for CHB patients. Yet, based on the usage of immune therapeutic agents, the near future might hold the positive news that immune therapy can be an acceptable innovative therapy for CHB patients.
- 1. The concept of “Elimination of Hepatitis by 2030” was approved and ratified by most countries in 2015.
- 2. The idea has several clear and specific targets.
- 3. The prevention target is optimistic and may be attained by 2030.
- 4. However, the estimated number of CHB patients has increased from 257 million in 2015 to 296 million in 2020.
- 5. More than 90% of these patients are unaware of their infection.
- 6. The major challenge of the program is discovering these “Missing Millions”.
- 7. Moreover, commercially available antiviral therapy may not be suitable to fulfill the therapy target of “Elimination of Hepatitis by 2030”.
- 8. New, safe, innovative, efficacious, and evidence-based drugs must be developed to ensure that targets are met.
While there is considerable optimism about attaining the HBV prevention target by 2030, the existence of millions of non-diagnosed CHB patients remains a significant source of concern. Even if we somehow proceed to find some percentage of the undetected CHB patients, it should be noted that no amicable treatment regimen exists for those living in developing and resource-constrained countries. Moreover, the nature of the available antiviral drugs and their infinite usage blocks their general utility. It is, however, assumed that new, innovative, and evidence-based drugs will be discovered and change the paradigm of CHB management. Overall, although we are not optimistic about the outcomes of the “Elimination of Hepatitis by 2030” plan in all relevant sectors, new discoveries and innovations may alter the picture.
The study was supported in part by a grant-in-aid from Japan Agency for Medical Research and Development (No. 20fk0310103h1904).
Sheikh Mohammad Fazle Akbar conceived the manuscript. Mamun Al Mahtab, Sakirul Khan, Osamu Yoshida, and Yoichi Hiasa acquired the data and drafted the primary manuscript. Sheikh Mohammad Fazle Akbar revised and edited the manuscript. All the authors approved the final manuscript.
Conflicts of Interest
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