Hepatitis B virus in Egypt: the whole story

Hepatitis B virus (HBV) infection is a significant global public health threat with variable geographical distribu‑ tion. Chronic infection with HBV could be complicated by chronic hepatitis state, progression to liver cirrhosis, and the development of hepatocellular carcinoma (HCC). For years, the magnitude of HBV problem in Egypt was masked by the great prevalence of hepatitis C virus in the country. The exact epidemiological data regarding HBV in Egypt are defective. The prevalence rate of HBV in Egypt has declined after the universal immunization program introduced for infants in 1992. This review addresses the whole story of HBV in Egypt: the epidemiology, risk factors, vaccination programs, and treatment efforts.


Introduction
Hepatitis B virus (HBV) infection is a significant and escalating global health concern [1].The World Health Organization (WHO) states that the prevalence of HBV varies across different geographic regions.In America, the prevalence is reported to be 0.7%, whereas in African and Western Pacific countries, it is estimated to be 6% [2].The consequences of HBV infection include the development of chronic hepatitis, the progression to liver cirrhosis, and hepatocellular carcinoma (HCC) [2].HBV accounts for around 33-50% of all HCC cases, resulting in an estimated 420,000 cases annually [3].In Egypt, there are approximately 8-10 million individuals who are affected by viral hepatitis, with millions more being susceptible to infection [4].Egypt ranks fifth globally in terms of the burden of viral hepatitis in 2009 and 2013, with an estimated 3.3 million individuals infected with HBV [5,6].This prevalence is classified as moderate endemicity; nevertheless, it is worth noting that the prevalence of HBV has experienced a drop in Egypt since 1992, which might be attributed to implementing a universal immunization program specifically targeting newborn infants [7].The incidence of HBV infection among adults and children in Egypt was recently reported to be 1.4% and 1.6%, respectively [8,9].The prevalence rates varied across various parameters, including age and gender [8].However, it is evident that the knowledge of the current state of HBV infection in Egypt is deficient [10].Despite the observed decrease in the burden of HBV, it continues to persist as a prominent public health issue in Egypt.The current review details the current state of HBV in Egypt, previous initiatives undertaken, and the persisting challenges that remain to be addressed.

HBV: virological characteristics
HBV is a hepatotropic and enveloped virus that has the potential to induce both acute and chronic hepatitis in human hosts [11], and it belongs to the Hepadnavirus family [12].HBV is divided into ten distinct genotypes (A-J) and four serotypes (adw, adr, ayw, and ayr), each with many sub-genotypes.These genotypes and serotypes exhibit geographical variations [13].The structural and functional variations in genotypes can potentially impact the progression, intensity, and pattern of sequelae, as well as the seroconversion of hepatitis B e antigen (HB e Ag), the response to antiviral therapy, and the efficacy of vaccination against the virus [14].
A study conducted in Egypt indicated that HBV genotype D is the predominant genotype among Egyptian carriers.This finding was based on the analysis of 105 blood samples isolated and sequenced for genotype determination [15].In their study, Naito et al. (2001) examined two serum samples that tested positive for HBV DNA using primer-specific PCR.The identified genotypes of these samples were found to be of genotype D. However, it is important to note that the study did not investigate the presence of additional genotypes, as only two serum samples were analyzed [16].Additionally, it has been reported in several reports later that genotype D was found to be the prevailing HBV genotype among Egyptian patients, accounting for 37.1% of cases, followed by genotype B (25.7%) [17].
Similarly, a study conducted in 2011 with a sample of 140 patients infected with HBV across various categories, including acute HBV patients, chronic active hepatitis patients, and patients with HBV-related HCC, revealed that 87% of the total samples were of genotype D, whereas 13% exhibited mixed genotypes D and F [18].However, a study conducted in Tanta City from 2014 through 2015 revealed that genotype E was predominant in 50% of the samples that tested positive for hepatitis B surface antigen (HBsAg).Genotype D was observed in only 21.43% of the samples, while a mixed infection of genotypes E and D was found in the remaining 28.57% of the patients [19].El-Mowafy et al. (2017) conducted a study in Mansoura City and found that genotype D (specifically sub-genotype D1) was present in all examined samples [20].Multiple reports from Egypt have provided evidence supporting the correlation between occult HBV infection (OBI) and genotype D, which was not the case with other genotypes [21].
Double infection with two distinct genotypes of HBV has been documented after the implementation of serological typing [22].The occurrence of superinfection with HBV isolates of either the same or different genotype has also been recognized in patients with chronic HBV infection [23].The occurrence of simultaneous infections with two distinct genotypes of HBV has been observed in a varying proportion of patients diagnosed with HBV infection, ranging from 4.4% [24] to 17.5% [25].Triple infections with HBV genotypes A, B, and C have been documented in 0.9% of intravenous drug users who are infected with HBV [25].Numerous clinical studies have demonstrated comparable treatment responses across various HBV genotypes for lamivudine, adefovir, entecavir, and telbivudine [26,27].A recent meta-analysis has indicated no discernible variation in the response rates when comparing different HBV genotypes and nucleos(t) ide analogs [28].At present, various techniques are available for the determination of HBV genotypes, such as direct sequencing [29], line-probe test [30], and PCR utilizing type-specific primers [16].Direct sequencing is the most precise technique since it identifies common and rare mutations.However, it is essential to note that this method is also associated with higher costs and requires meticulous attention to detail [31].

HBV epidemiology
Globally, an estimated 248 million people are chronically infected with HBV [32].The WHO estimates that in 2019, about 296 million people worldwide were living with HBV, and 1.5 million people were newly infected with chronic HBV [33].African and Western Pacific regions have the highest burden (6.1% and 6.2% in the general population) [34].
According to the Egypt Health Issues Survey (EHIS) conducted in 2015, the prevalence of chronic HBV infection among the population of Egypt aged 1 to 59 years is 1% [35].Meanwhile, some literature estimated the prevalence of HBV in Egypt to be less than 2% [32].However, seroprevalence estimates of HBsAg among pregnant women in some rural regions of Egypt range from 4% to as high as 8% [36].Limited information is available regarding the prevalence of HBV among various populations at risk in Egypt in comparison to hepatitis C virus (HCV) [37].The prevalence of HBV in Egypt showed a progressive decline over time as an effect of introducing the HBV vaccine to the list of compulsory vaccinations for infants.A comprehensive analysis was conducted to examine the prevalence of HBsAg in the general population of Egypt across the period spanning from 1980 to 2007, encompassing both the pre-vaccination era and the post-vaccination era.The reported prevalence rate of HBsAg in 2007 was 6.7%, lower than the rates observed in the 1980s [6].The cross-sectional study conducted in 2015 (EHIS) to estimate the prevalence of HBV infection among Egyptians aged 15-59 included a sample size of 15,777 individuals.The overall infection rate was 1.4%, with a greater prevalence observed among men (1.9%) compared to women (1.1%) [38].Among the fever hospitals that were included in reporting HBV cases during the period from 2014 to 2017, the prevalence of HBV infections was found to be the highest in Abbasia (5.8%) and Aswan (4.3%) hospitals [35].

Risk factors for HBV infection in Egypt
The primary mode of HBV transmission in Egypt is community-based rather than resulting from medical intervention.A case-control study conducted in Greater Cairo revealed that the practice of shaving among males at barbershops was linked to a twofold increase in the risk of HBV infection.This finding is of concern, particularly given that most males (specifically, 64% of controls in this study) still opt to have shaves at barbershops [39].Shaving is a widely recognized risk factor for both HBV [40] and HCV [41].Barbers sometimes lack knowledge of the concept of blood-borne transmission, leading to the reuse of razors and scissors on several customers without proper sterilization [42].An area of danger that warrants additional investigation is the practice of "hijama, " also known as wet cupping, which involves the extraction of blood through a small incision in the skin using a vacuum for therapeutic purposes.Professional barbers commonly carry out the initial shaving of the area, which is crucial for achieving a secure seal with the cup [39].Another vital contribution to HBV transmission in the same study was intravenous drug use; 13% of controls acknowledged drug use, and almost 3% admitted intravenous drug use [39].Numerous studies have consistently demonstrated a significant correlation between intravenous drug use (IVDU) and the probability of HBV transmission [37,39].The available data on the role of sexual contact in transmitting the disease is currently limited, and the existing studies rely on simplistic measures of sexual activity, such as marital status [39].However, it is worth noting that intra-familial transmission through this method has been reported [43].The presence of a family history is a significant risk factor for contracting HBV infection, as has been previously established in various reports [44,45].Several other significant risk factors for HBV transmission have been found, including exposure to dental treatments, sutures, acupuncture, tattoos, body piercing, and literacy [6], and invitro fertilization [46].The prevalence rate of HBV infection among pregnant women in Upper Egypt, which stands at 5% in one study, justifies the need for universal screening of all women throughout pregnancy [47].Transmission from the infected mother to her child primarily happens during childbirth; however, it could also occur in utero through the leakage of the virus through the placenta [48].In a prior cohort study involving 901 asymptomatic women in labor, it was found that 4.8% of them tested positive for HBsAg.The estimated rate of vertical transmission of HBV during birth was approximately 1.7%, leading to chronic antigenemia in 0.6% of births.Additionally, 17.2% of these children experienced horizontal transmission of HBV within the first year of life [49].The most prevalent method of transmission on a global scale is perinatal transmission [50].

HBV as a significant risk factor for HCC development
HCC is the prevalent type of liver cancer, ranking sixth in terms of global incidence and third in terms of cancer-related mortality in 2020.The year saw an estimated 906,000 new cases and 830,000 deaths attributed to HCC [51].HBV infection accounts for 50-80% of HCC incidences globally [52].Incorporating HBV viral DNA into the host's genetic material is an essential molecular mechanism contributing to the development of HCC.Studies have shown that the HBV DNA integration into the host's chromosomes is observed in around 85% to 90% of tumor cells found in HCC patients [53].Many reports have demonstrated the significant involvement of miRNAs in both the replication of HBV and the onset and progression of HCC associated with HBV [54].Several microRNAs (miRNAs) have been found to facilitate the replication of HBV in distinct ways [54,55].
Furthermore, it has been observed that HBV can induce epigenetic alterations through modulating DNA methylation and histone post-translational modifications.These molecular changes are crucial in developing HCC associated with HBV infection [56].Furthermore, a significant proportion (about 66%) of patients diagnosed with HCC have an aberrant activation of the Wnt/β-catenin signaling pathway [57].Consistently elevated levels of HBV DNA and alanine aminotransferase (ALT) have been identified as robust and autonomous predictors of HCC associated with HBV [58].HBV viral replication has been found to increase the likelihood of developing cirrhosis and HCC [59].The occurrence of HCC in patients with chronic HBV without cirrhosis is higher than that observed in the general population.Furthermore, the incidence of HCC varies across different geographical regions.For instance, among Europeans, the annual incidence is less than 0.2%, whereas in Asians, it ranges from 0.4% to 0.6% per year [60].The risk of HCC is significantly amplified by the presence of cirrhosis, with an increase of more than ten times [60].Nevertheless, in Egypt, the primary risk factor for HCC remains HCV, although the extent of its link with HCC development is still a subject of debate [61].

Occult hepatitis B virus infection: the rising challenge
Occult hepatitis B infection (OBI) refers to identifying HBV genetic material in the blood or liver tissue of patients who test negative for HBsAg [62].The molecular underpinnings of OBI involve the prolonged presence of viral covalently closed-circular DNA within the nuclei of hepatocytes [63].Patients with OBI have the potential to exhibit either seropositivity or seronegativity.Seropositive OBI is distinguished by the presence of anti-hepatitis B core antibodies (anti-HBc), with or without anti-hepatitis B surface antibodies (anti-HBs).On the other hand, seronegative OBI is characterized by the absence of both antibodies [64].The predominance of seropositive OBI is mainly attributed to the higher prevalence of resolved HBV infection [64].A significant proportion, exceeding 20% of patients who have OBI, exhibit seronegativity for all HBV indicators [62,64].Anti-HBc is recommended as an alternative surrogate marker when sensitive HBV-DNA testing is not readily accessible [65].The clinical implications of OBI are associated with its potential transmission through blood transfusion or liver transplantation, resulting in HBV in the recipient.Additionally, viral reactivation can occur in OBI patients with compromised immune systems and can fasten cirrhosis progression.Furthermore, OBI plays a significant role in developing HCC [66].
The global prevalence of OBI exhibits significant variability [67].Increasing data suggests a favorable link between the prevalence of OBI and the endemicity of HBV [62].Furthermore, chronic HCV patients have a higher incidence of OBI [62,64].Moreover, HBV-DNA can be detected in approximately one-third of patients who test negative for HBsAg but are carriers of HCV in the Mediterranean region [62,64].There is a significant prevalence of OBI among HCV patients with advanced liver disease, even in regions with lower rates of HBV endemicity [62].OBI is rare among blood donors in the Western world, but it is more prevalent in underdeveloped countries [62].The frequency of OBI among HCC patients who test negative for HBsAg and anti-HBC ranges from 16% in the United States to 70% in regions with high HBV endemicity, such as China [68].A high frequency of OBI has been seen in patient populations with known risk factors for HBV infection.These risk factors include people who inject drugs (45%) [69], those with coinfection of HCV (15-33%) [70] or human immunodeficiency virus (HIV) (10-45%) [71,72], and patients on hemodialysis (27%) [73].Patients with co-existing liver disease, such as HCC (63%) [74], cryptogenic cirrhosis (32%) [75], or liver-transplant patients (64%) [76], have also demonstrated higher prevalence rates of OBI.
In Egypt, Lehman et al. encountered difficulties in conducting a comparative analysis of OBI prevalence between Upper and Lower Egypt.This challenge arose from insufficient HBV prevalence studies focusing on Upper Egypt [77].The prevalence of OBI in Upper Egypt was only investigated in two studies [18,19].The prevalence of OBI among hemodialysis patients in Upper Egypt is significantly lower (4.1%) compared to patients in Lower Egypt (26.9%) [78,79].There is a notable increase in the frequency of HCV among patients residing in Lower Egypt.This finding supports a positive association between HCV and OBI rates [6].The frequency of OBI among adults in Egypt varies from 0.48% [80] to 58.3% [81].The prevalence of occult OBI in children was found to be significant in several studies.OBI was detected in 32% [82], 32.5% [83], and 21% [84] of children with cancer who were also positive for HCV, thalassemic children, and children with hematological malignancies, respectively.The frequency of OBI among hemodialysis patients in Egypt varies between 4.1% and 26.9% [78,79].Another Egyptian study demonstrated that 58.3% of patients with symptomatic hepatitis were diagnosed with OBI [81].A study conducted on HCC patients in Egypt revealed a high prevalence of OBI (62.55%) [74].

HBV coinfections HBV/HCV
Chronic HBV and HCV infections are a substantial public health issue, with a noticeable variance in different regions.Coinfection with both viruses differs according to the prevalence of both viruses in each geographical region [77].The occurrence of HBV/HCV coinfection in Egypt is about 0.7% [85].Around 10-15% of individuals with chronic HBV infection also have HCV infection, and around 2-10% of individuals who test positive for anti-HCV antibodies are also positive for HBsAg [86].Individuals afflicted with HBV/HCV coinfection face an elevated likelihood of developing cirrhosis and decompensated liver disease [87], as well as an augmented danger of HCC [88].HCV superinfection is common in regions with a high prevalence of HBV infection, including Asia, South America, and Sub-Saharan Africa [89].The prevalence of coinfection is 16% in an Indian study, 1.7% in an Egyptian study, 1.7% in a Brazilian study, 2.6% in a Turkish study, and ranged from 10% to 15% in studies originating from Spain, Italy, Japan, Taiwan, and Iran [85,[90][91][92].Patients with HBV/HCV coinfection are eligible for treatment with DAAs targeting HCV [93].The factors that were found to be independently associated with HBV/HCV coinfection were the age of 50 years or younger, male gender, positive HIV status, history of hemophilia, sickle cell anemia or thalassemia, history of blood transfusion, and cocaine and other drug use.On the other hand, patients of Hispanic origin had a decreased risk of coinfection [93].

HBV/hepatitis D virus (HDV)
In a study conducted by Gish et al. in the United States, 8% of patients with chronic HBV were verified to have HDV coinfection [94].The occurrence of HDV varies throughout different regions of the world and is more elevated in Eastern Europe and Western Asia [94].Fouad et al. showed a significant prevalence of HDV in patients with negative HBeAg status, emphasizing its role in reducing HBV replication [95].Another cross-sectional study found that 43% of individuals who tested positive for HBsAg also tested positive for anti-HDV.Among the 80 patients who tested positive for Anti-HDV, HDV RNA was detected by PCR in 25 cases, accounting for 31.3% of the Anti-HDV-positive cases.Therefore, the prevalence of HDV using PCR was determined to be 13.4% (25 out of 186 cases) in Upper Egypt [96].El Zayadi et al. found that among patients with chronic liver disease who tested positive for HBsAg, 47.7% (21 out of 44) had HDV.They also found that among individuals who were carriers of HBsAg, 8.3% (4 out of 48) had HDV [97].According to Abdel-Fattah et al., the prevalence of HDV was 8.9% [98].Darwish et al. reported that 16.94% of individuals with acute HBV infection, 23.53% with chronic HBV infection, and 21.9% of individuals who carry the HBsAg antigen have tested positive for HDV antibodies [99].Another study from Egypt involving a group of 45 Egyptian children (aged 2-15 years) reported that four of them (8.9%) tested positive for IgG anti-HDV [100].A more recent study conducted in Lower Egypt found that 8.3% of chronic HBV-infected patients had HDV, as determined by the presence of anti-HDV IgG.Additionally, 9.9% of patients tested positive for HDV by PCR [95].

HBV-HIV
HIV coinfection alters the natural features of HBV infection through modifying genome replication status, increasing rates of chronic infection, and liver disease progression [101].HIV has a significant effect on HBV, as it can trigger chronic active HBV infection, which in turn can result in an increased risk of HCC [102].A history of HBV infection has been recorded in over two-thirds of individuals infected with HIV, indicating a high rate of coinfection with HBV and HIV [103].The frequency of chronic HBV infection among HIV patients varies, ranging from 5% to 10% in Western countries, while the estimated prevalence of HIV-HBV coinfection is roughly 20%, either through drug injection or sexual transmission [104].The rates of HIV-HBV coinfection among people who inject drugs (PWID) rise as they get older [105].In Asia and sub-Saharan Africa, the prevalence of HIV-HBV coinfection is moderate to high, ranging from 10% to 20%., mainly observed during the perinatal period and early infancy [104,106].In Egypt, a study found that HBsAg was present in 4 individuals (2.4%), while anti-HBc was discovered in 49 individuals (29.2%) among a cohort of HIV patients [107].The same study revealed a substantial correlation between past infection with HBV (indicated by positive anti-HBc and negative anti-HBs) and many factors, including female genital mutilation circumcision, injectable drug usage, invasive medical operations, non-specific fatigue, and seropositivity for HCV antibodies [107].The primary treatment for patients with HIV-HBV coinfection is HBV-active antiretroviral therapy (ART), typically involving the use of tenofovir in combination with either lamivudine or emtricitabine.This treatment has considerably reduced the presence of HBeAg and HBsAg antigens in infected patients [108].

HBV in healthcare workers (HCWs)
HCWs had a fourfold higher risk of HBV infection compared to the general population [109].This could be attributed to noncompliance with recognized guidelines for infection control, such as those set by the Centers for Disease Control and Prevention (CDC) [110].Adhering to the CDC's guidelines, practicing hand hygiene, utilizing gloves, and properly disposing of sharp tools are all essential measures to avoid the transmission of HBV [110], while risk factors include geographical location and other host variables [109].In developing countries, occupational infections are common due to the high prevalence rates of blood-borne pathogens and the increased risk of injury [111].A study that investigated occupational exposure to needle sticks and sharp medical device injuries and HBV in Egypt (the Nile Delta and Upper Egypt regions) revealed that around 8617 cases of HBV infections are reported annually among HCWs [112].Another study conducted among HCWs in a national liver disease referral center in Egypt found that 16.6% of HCWs tested positive for HCV-Ab, 1.5% tested positive for HBs-Ag, and 0.2% tested positive for coinfection [113].Additionally, an Egyptian study revealed that the rates of anti-HBs varied among different occupational groups, with nonprofessional personnel having the highest frequency (60%), followed by graduated nurses (33%) and physicians (29%) [114].However, Egyptian HCWs do not undergo regular screening for HBV infection [19].

Pregnant women
Approximately half of the cases of HBV infection are acquired either during childbirth or in early infancy, particularly in areas where HBV is prevalent [115].Perinatal vertical transmission is the predominant method of transmission globally [50].The likelihood of perinatal infection is between 5% and 20% in infants born to mothers who test positive for HBsAg and between 70% and 90% if the mother is positive for HBeAg [116,117].Screening pregnant women for HBsAg is necessary to prevent virus transmission from mother to child.This screening helps determine which newborns should get immunization [118].A report from Libya and Algeria has indicated a low occurrence of HBV (1.5-1.6%)among pregnant women [119].In contrast, Saudi Arabia and Pakistan have shown more prevalence of HBV, with HBsAg rates of 4.1% and 4.6% respectively [120].A significantly greater occurrence was documented in prenatal clinics in Sudan and Nepal [121,122].Vertical transmission of HBV infection is a significant and problematic risk factor for infants born in Egypt after the mass vaccination era [47].According to Badawy and El-Salahy's findings, the percentage of transmission from HBsAg-positive women to their babies is 51.8% in Egypt [123].The prevalence of HBsAg in upper Egypt in 1993 was 14.7%, which is higher than the rates reported by Alrowaily et al. [124] and Al-Mazrou et al. in Saudi Arabia (1.6% and 2.6%, respectively) [125].Implementing early universal HBV immunization in infancy in Saudi Arabia in 1990 and Egypt in 1992 could cause such a reduction in prevalence figures [125].A previous report from Assiut, Upper Egypt, documented a 4% prevalence rate of HBsAg in pregnant women [126].Newborns from mothers with known HBV infection get HB immunoglobulin and the vaccination within 12-24 h after birth, resulting in a 95% reduction in the chance of acquiring HBV [127].However, the effectiveness of such an approach is diminished for mothers with high HBV viremia (> 10 8 IU/mL) [128].The inability to prevent HBV transmission from mother to child is affected by the positivity of the mother to HBeAg [27,28] and a maternal HBV DNA level of ≥ 10 7 copies/mL [129].Additionally, the prevalence rate of HBV in pregnant women over the age of 25 is higher than in those under the age of 25 [120].Nevertheless, Eke et al. reported the highest prevalence of HBsAg among pregnant women aged 20-24 years [44].HBV was more prevalent in women above the age of 29 in other studies [130].

Hemodialysis patients (HD)
Hemodialysis patients (HD) are at high risk for acquiring HBV and HCV infections due to frequent blood transfusion and exposure to infected patients besides contaminated HD machines and equipment [131].In Egypt, about 19% (28/150) of patients undergoing HD had evidence of HBV infection, and 22/28 (78.6%) of them had genotype D [132].In another study of 144 HD patients, about 12 had positive hepatitis B viral nucleic acid (8.3%) [133].In the Ismailia governorate of Egypt, 150 patients under HD were tested for HBV-DNA.It was shown that 10% of the patients had overt HBV infection, while 7.3% had seropositive occult HBV.Among those with occult infection, the majority showed only HBcAb antibodies [132].

HBV and abnormal sexual behaviors
HBV is transmitted via sexual intercourse, specifically through heterosexual and male-homosexual interaction [134].Heterosexual transmission commonly occurs in various contexts, such as engaging in sexual activities with female sex workers in impoverished nations [135].Evidence indicates that approximately 10% of HBV cases can be attributed to homosexuality [136].While the prevalence of HBsAg carriers is higher in males than females, it is essential to note that transmission of HBV among women may still occur [137].Women who engage in high-risk behaviors, such as having sex with males, having many bisexual partners, and entering into contract marriages (marriages between gay men and lesbian women), are present within the population of women who have sex with women (WSW) [138].A cross-sectional study conducted from December 2016 to March 2017 involved interviewing and testing 52 Egyptian female sex workers (FSWs) for HBV, HCV, and HIV markers.Out of the participants, two cases (3.8%) tested positive for HCV antibodies, while 10 (19.2%) and 5 (9.6%) had detectable levels of anti-HBs and anti-HBc, respectively.The study found that 78.8% of the participants were susceptible to HBV infection, and none of them had HIV antibodies [107].

HBV map in Egypt has been changing over decades now
The prevalence rate of HBV declined after the universal immunization program for infants in Egypt in 1992 to (1.3-1.5%)[139].In the early 1980s, HBV demonstrated a high prevalence, identified in 10.1% of the entire Egyptian population [7].A meta-analysis reporting the period between (1980 and 2007) demonstrated a 6.7% prevalence of HBsAg in Egypt, which was a lower rate than that in the 1980s [6], while in 2015, it was 6.3% [8,140].The plan began in the early 1990s with a screening of blood donors [141].Then, in 1992, Egypt added the HBV vaccine to the compulsory Egyptian list of vaccinations [142].
This preventive control plan promoted safe practices in hospitals and healthcare facilities in 2003 [141].Besides, to increase awareness, implement infection control measures in healthcare facilities and train HCWs [141].

Egypt MOH efforts for HBV prevention
HBV vaccination is the primary strategy for preventing HBV infection [143].The WHO recommended the global universal childhood immunization in 1992.By the end of 2012, 181 countries had adopted this approach [143].The objective of the HBV immunization program is to attain durable immunity through the administration of the HB vaccine.Additionally, it aims to assess the occurrence of breakthrough infections (shown by positive anti-HBc) and the development of chronic carrier status (indicated by positive HBsAg) in patients who have been previously vaccinated [144].The yeast-dependent recombinant HBV vaccine was used in Egypt in 1992 as part of the HBV vaccination program.The vaccine was administered to infants aged 2, 4, and 6 months [145].Initially, no serosurveys were conducted on children born after the vaccination was introduced in Egypt.However, the discovery of active disease transmission in these groups suggests that HBV transmission is still occurring.Therefore, a more comprehensive assessment of the immunization program is necessary [146].
In one study, the percentage of children protected against the disease through antibodies was found to be 57.2%.This rate dramatically reduced from 90.2% in children under 3 to 30.5% in children aged 15 and above [147].Another study conducted in Egypt found that the seroprotection rate among vaccinated children aged 6 and 12 years was 54% and 39.7%, respectively [142,148].When neonates of mothers who are positive for HBsAg are given both active and passive immunization against HBV, they maintain long-lasting protection against the virus until adolescence, even if the levels of anti-HBs antibodies often decrease over time [149].A recent meta-analysis indicated that the HBV vaccination alone appears as efficacious as a combination of HBIG and HBV vaccine in preventing infection in neonates born to HBsAg+/HBeAg-mothers [150].The complete vaccination regimen elicits sufficient protective antibodies in over 95% of newborns, children, and young adults.This immunity persists for at least 20 years and may last a lifetime [151].

Expert views for filling the gaps
Screening high-risk groups appears to be an extremely important approach to eliminate HBV from Egypt.Regular HBsAg screening and anti-HBc and/or HBV DNA testing for Egyptian health care workers, chronic infected patients with HCV, HDV and HIV, in addition to screening for HBsAg in pregnant women at their first antenatal visit in all public healthcare facilities.Similarly, regular screening for HBsAg, anti-HBc, and HBV DNA in high-risk populations (hemodialysis patients HD patients, patients with thalassemia, patients receiving immunosuppressive therapies, and homosexuals) should be seriously included in healthcare services.Additionally, we have to consider a booster dose of vaccination in healthy individuals later in their future life.In a country with a long history of battels with liver diseases, there is a need to enhance awareness in all social classes about the nature of the virus, incubation period, mode of transmission, and prevention.