Prevalence of hepatitis B e antigenemia in Bahraini hepatitis B patients: A retrospective, single‐center study

Abstract

Background and Aim

Hepatitis B e (HBe) antigen (HBeAg) is commonly encountered among hepatitis B patients and is indicative of active infection. There is a lack of data in the literature about the prevalence of HBeAg among hepatitis B patients in Bahrain and its impact on the disease. The aims of this study were to investigate the prevalence of HBeAg among a sample of hepatitis B patients in Bahrain and to analyze their associated laboratory profile, radiological characteristics, comorbidities, and complications.

Methods

This was a retrospective record‐review study conducted on patients' records at Salmaniya Medical Complex hospital in Bahrain during the period of 2011–2016. All records of hepatitis B patients who had HBeAg tests performed were included in this study.

Results

Of 323 patients recruited, 18.9% had positive HBeAg. The prevalence of anti‐HBe antibodies and hepatitis B core immunoglobulin G (HBc IgG) differed significantly between patients with positive and negative HBeAg (P < 0.001, P = 0.026, respectively). Alanine transferase and gamma‐glutamyl transferase were significantly higher among patients with positive HBeAg (P = 0.017, P = 0.016, respectively). There was no significant difference with regard to the prevalence of hepatitis C virus, human immunodeficiency virus, hepatocellular carcinoma, or liver transplantation between HBe‐positive and ‐negative patients (P ≥ 0.05).

Conclusion

HBeAg is prevalent among hepatitis B patients in Bahrain and is associated with a significantly different laboratory profile.

Introduction

Hepatitis B e antigen (HBeAg) is one of the small polypeptides detected in the sera of patients with hepatitis B virus (HBV). ¹ , ² It is detected shortly after the appearance of hepatitis B surface (HBs) antigens, rising rapidly during the early stage of infection and swift viral replication. ¹ Thus, the existence of HBeAg in patients' sera correlates with the degree of infectivity of the HBV and with the number of infectious virions. ¹ In many studies, the HBeAg level in patients' sera also correlates with the existence of hepatitis B core (HBc) antigens in hepatocytes. After the infection quietens, the level of HBeAg declines gradually until it becomes undetectable during the recovery of acute hepatitis B infection. Meanwhile, hepatitis B e (HBe) antibodies increase and remain positive for several years after resolution of the acute hepatitis. ¹

Evaluation of the state of HBeAg positivity in hepatitis B patients is an essential indicator for infectivity and the viral replication state. ³ , ⁴ From a patient perspective, it provides information about the development of anti‐HBe immunity, a turning point in the battle between HBV and its host, and can be used to monitor response to treatment. The mode of transmission and the clinical course of HBV infection can also be determined by the length of the HBeAg‐positive phase. ⁴ In addition, HBeAg status is incorporated in management guidelines internationally, ³ , ⁵ where it directs treatment choices and decisions to discontinue treatment. ⁶ Knowing the infectivity of patients with HBV can also help plan further measures for disease control because the primary mode of transmission is person to person, either through vertical or horizontal transmission. ⁷ In Bahrain, 61% of infections were estimated to be due to dental procedures and surgical operations, followed by blood transfusions (24%). ⁸

In Bahrain, the prevalence of HBV infection was reported to be 0.58%, with the number increasing over the past few years. ⁸ The most common HBV genotypes reported among this population are genotypes D (61%) and A (10%). ⁹ Epidemiological data relating to HBeAg in any population would provide important data about the infectivity of the disease and the importance of disease control. ¹ To the best of our knowledge, there is a lack of data in the literature about the prevalence of HBeAg positivity among hepatitis B patients in Bahrain.

Objectives

The aims of this research were to study the prevalence of HBeAg among hepatitis B patients in Bahrain and to study the impact of the existence of these antigens on the laboratory profile; radiological characteristics; and hepatitis complications, such as cirrhosis, hepatocellular carcinoma (HCC), or liver transplantation.

Methods

This was a record‐review study conducted in Salmaniya Medical Complex (SMC) in Bahrain during the period 2011–2016. Bahrain has a universal health‐care system, and the government provides free health care to Bahraini citizens and subsidized health care for non‐Bahrainis. The SMC hospital is the main public hospital in the country and is considered a tertiary hospital that serves the whole nation, a population of 1.7 million as of 2020. The SMC hospital has all specialties available and receives referrals from other government hospitals, private hospitals, and health centers (including primary care) scattered all over the country. The hospital is considered the main center for the treatment of hepatitis B as all treatments are available, and therefore, it receives referrals for patients with hepatitis.

The records that were eligible for inclusion in this study were only those of hepatitis B patients who had undergone HBeAg testing. Demographic data were collected from all records (e.g. age and gender). Laboratory data included HBeAg, anti‐HBe antibodies (anti‐HBe Ab), HBs antigen (HBsAg), HBc immunoglobulin M (HBc IgM), HBc immunoglobulin G (HBc IgG), HBV DNA level, hepatitis C virus (HCV), human immunodeficiency virus (HIV), alanine transferase (ALT), alkaline phosphatase (ALP), gamma‐glutamyl transferase (GGT), bilirubin, albumin, urea, and creatinine. Data from hepatic imaging were also gathered. Details on comorbidities were recorded, which included diabetes mellitus, hypertension, hyperlipidemia, HCV, liver or renal transplant, HIV, hypothyroidism, lymphoma, inflammatory bowel disease (IBD), and solid organ caner.

All data were fed into the computer and analyzed using the Statistical Package for Social Science (SPSS) software, version 23.0 (IBM, Armonk, NY, USA). ¹⁰ Categorical variables were presented as frequencies and percentages. Continuous variables were presented as means ± SDs. Chi square, Fisher's extract, and student‐independent t tests were used for comparison of means between patients with positive and patients with negative HBeAg depending on the normality of variables. The comparison between the two groups was made in regard to the demographic data, the lab profile, the radiological characteristics, the associated comorbidities, and the associated complications. Statistical analysis was performed at the 0.05 level of significance.

Results

Of 323 hepatitis B patients recruited, 18.9% (n = 61) had positive HBeAg. The mean age of patients did not differ between the HBeAg‐positive (45.3 ± 15.9 years) and the HBeAg‐negative (46.3 ± 14.5) groups (P = 0.62). Males constituted 59% of the whole sample (Table 1). Most of the HBe‐positive group (86.9%) had an HBV DNA level of less than 10⁴ IU/mL. For the HBe‐negative patients, 86.6% had HBV DNA levels below 2000 IU/mL (Table 2).

Table 1.

Demographic data among the studied groups (n = 323)

	Hepatitis B e antigen (HBeAg) positive	HBeAg negative	Statistical test	P‐value
	(n = 61, 18.9%)	(n = 262, 81.1%)
Age
M (SD)	45.3 (15.9)	46.33 (14.3)	t = 0.5	0.620
(Min, Max)	(16, 82)	(19, 88)
Gender
Male	36 (59.0)	191 (59.1)	χ 2 = 0	0.984

Values are number and (%) unless otherwise is specified.

χ ²: Chi‐square test; t: Independent t‐test.

Table 2.

Distribution of hepatitis B virus DNA (measured in IU/mL) among the studied groups (n = 323)

Hepatitis B e antigen (HBeAg) status	HBeAg +ve			HBeAg −ve
Hepatitis B virus (HBV) DNA	<104	104 to 107	>107	<2000	>2000
n	53	3	5	226	35
(%)	(86.9)	(4.9)	(8.2)	(86.6)	(13.4)

Upon comparison of the virology profile between patients with positive and negative HBeAg, HBs antigens and HBV DNA positivity were not significantly different among the two groups (P = 0.97). Patients who were HBeAg positive had higher loads of HBV DNA than HBeAg‐negative patients, although the difference was not statistically significant (P = 0.09). Anti‐HBe Ab were not detected in any of the HBeAg‐positive group, but they were detected in 84.4% of the HBeAg‐negative group (P < 0.001). HBc immunoglobulins were also significantly different between the two groups. HBc IgM was significantly higher among patients with positive HBeAg (6.6% vs 1.1% in patients with negative HBeAg) (P = 0.026), while HBc IgG were significantly lower (96.7% of HBe‐positive patients vs 100% of HBe‐negative patients) (P = 0.035) (Table 3).

Table 3.

The virology profile among the studies groups (n = 3232)

	Hepatitis B e antigen (HBeAg) positive		HBeAg negative		Statistical test	P‐value
	(n = 61, 18.9%)		(n = 262, 81.1%)
Anti‐hepatitis B e antibodies
+ve	0	0.0	221	(84.4)	χ 2 = 162.94	<0.001
Hepatitis B surface antigen
+ve	54	(88.5)	232	(88.5)	FET	0.996
Hepatitis B core (HBc) immunoglobulin M
+ve	4	(6.6)	3	(1.1)	χ 2 = 0.00	0.026
HBc Big
+ve	59	(96.7)	262	(100.0)	χ 2 = 0.00	0.035
Hepatitis B virus (HBV) DNA
Detected	37	(60.7)	196	(60.9)	χ 2 = 0.00	0.970
HBV DNA †
M (SD)	7.7 (4.6)		6.4 (2.5)		t = 1.73	0.092
(Min, Max)	(3.5, 18.7)		(2.7, 18.2)

^†DNA level among 37 HBeAg‐positive and 196 HBeAg‐negative cases only; in logarithmic scale.

Values are number and (%) unless otherwise is specified.

χ ², Chi‐square test; FET, Fisher's Exact test; t, independent t‐test.

On evaluation of the laboratory profile of the studied groups, a higher percentage of patients with positive HBeAg (54.1%) had ALT levels higher than 33 U/L in comparison to patients with negative HBeAg (P = 0.017). The percentage of patients with levels of GGT above 55 U/L was significantly higher among the HBeAg‐positive patients (32.8% vs 18.7%) (P = 0.016). Levels of ALP, bilirubin, albumin, urea, and creatinine were not significantly different between the two studied groups (P = 0.784, P = 788, P = 0.261, 0.767, and P = 0.096, respectively) (Table 4).

Table 4.

Laboratory profile among the studied groups (n = 323)

	Hepatitis B e antigen (HBeAg) positive	HBeAg negative	Statistical test	P‐value
	(n = 61, 18.9%)	(n = 262, 81.1%)
Alanine transferase
≥33 U/L	33 (54.1)	131 (40.6)	χ 2 = 5.72	0.017
M (SD)	106 (324.2)	69.1 (354.2)	t = 0.74	0.45
(Min, Max)	(7, 2429)	(8, 5126)
Alkaline phosphatase
M (SD)	94.8 (68.6)	91.5 (85)	t = 0.27	0.78
(Min, Max)	(7, 407)	(8, 960)
Gamma‐glutamyl transferase
>55 U/L	20 (32.8)	49 (18.7)	χ 2 = 5.84	0.016
M (SD)	89.9 (172.2)	53.6 (83.8)	t = 1.59	0.117
(Min, Max)	(6, 989)	(6, 555)
Total Bilirubin (T.BIL) †
<5 μmol/L	1 (1.6)	11 (4.2)	${\chi }_{\mathrm{lin}}^2=0.07$	0.788
5–21 μmol/L	50 (82.0)	204 (78.5)
>21 μmol/L	10 (16.4)	45 (17.3)
M (SD)	31.1 (75.1)	18.4 (36.8)	t = 1.29	0.201
(Min, Max)	(3, 464)	(2, 366)
Albumin ‡
<35 g/L	10 (16.4)	25 (9.7)	${\chi }_{\mathrm{lin}}^2=1.27$	0.261
35–52 g/L	50 (82.0)	234 (90.3)
>52 g/L	1 (1.6)	0 (0.0)
M (SD)	40.7 (8.3)	41 (5.5)	t = 0.28	0.782
(Min, Max)	(12, 69)	(16, 52)
Urea
<3.2 mmol/L	8 (13.1)	17 (6.5)	${\chi }_{\mathrm{lin}}^2=0.09$	0.767
3.2–8.2 mmol/L	43 (70.5)	224 (85.5)
>8.2 mmol/L	10 (16.4)	21 (8.0)
M (SD)	6.6 (5.7)	5.4 (2.5)	t = 1.54	0.127
(Min, Max)	(1.5, 36)	(1.8, 22.8)
Creatinine
Low	2 (3.3)	18 (6.9)	${\chi }_{\mathrm{lin}}^2=2.77$	0.096
Normal	41 (67.2)	189 (72.1)
High	18 (29.5)	55 (21.0)
M (SD)	97.4 (127.9)	79.9 (50.1)	t = 1.05	0.297
(Min, Max)	(37, 1039)		(32, 665)

^†T.Bil was available for all HBeAg +ve cases and for 260 HBeAg +ve cases.

^‡Albumin was available for all HBeAg +ve cases and 259 HBeAg +ve cases.

Values are number and (%) unless otherwise is specified.

χ ², Chi‐square test; ${\chi }_{\mathrm{lin}}^2$, ordinal Chi‐square test; t: independent t‐test.

The prevalence of comorbidities, HCV, HIV, cirrhosis on abdominal imaging, HCC and liver transplantation was not different between patients with positive and patients with negative HBeAg (Table 5).

Table 5.

Comorbidities and complications among the studied groups

	Hepatitis B e antigen (HBeAg) positive	HBeAg negative	Statistical test	P‐value
	(n = 61, 18.9%)	(n = 262, 81.1%)
Comorbidity
Yes	10 (16.4)	31 (11.8)	χ 2 = 0.93	0.335
Hepatitis C virus
>55 U/L	5 (8.2)	14 (5.3)	FET	0.373
Human immunodeficiency virus
Positive	1 (1.6)	1 (0.4)	FET	0.343
Imaging
Post Tx Normal	1 (1.6)	3 (1.1)	MC	0.764
Normal	37 (60.7)	154 (58.8)
Abnormal	23 (37.7)	105 (40.1)
Hepatocellular carcinoma
Positive	1 (1.6)	5 (1.9)	FET	1.000
Transplant
Yes	5 (8.2)	13 (5.0)	FET	0.351
On medication
Yes	27 (44.3)	88 (33.6)	χ 2 = 2.46	0.117
Type of medication †
Entecavtr	22 (81.5)	73 (27.9)	MC	1.000
Tenofovtr	5 (18.5)	14 (5.3)
Tacrolimus	0 (0.0)	1 (0.4)

^†Only among cases on medications.

Values are number and (%) unless otherwise is specified.

χ ², Chi‐square test; FET, Fisher's exact test; MCT, Monte Carlo correct Chi‐square test.

Of note, 44.3% of patients with positive HBeAg were on antiviral medications, whereas only 33.6% of HBeAg‐negative patients were on treatment. Entecavir was the most common antiviral drug used in both groups (prescribed to 81.5% and 27.9% of HBeAg‐positive and ‐negative groups, respectively). Tenofovir was prescribed to 18.5% and 5.3% of HBeAg‐positive and ‐negative groups, respectively. Tacrolimus was prescribed to a single patient with negative HBeAg (Table 5).

Discussion

Hepatitis B affects about 0.5% of the population in Bahrain, and the prevalence has reportedly been increasing in recent years. ⁸ Hepatitis B infection is a serious hepatic condition associated with considerable complications such as liver cirrhosis, hepatic failure, or HCC. ¹¹ Early and adequate treatment of the condition not only reduces such complications but also prevents the transmission of infection to other members in the community. ⁷

HBeAg is one of the secretory proteins formed from the hepatitis B precore protein and is therefore considered a marker of disease infectivity and viral replication state. ² Assessment of HBeAg positivity helps in the monitoring of disease activity and is also an indicator for the rate of transmission of the infection to contacts and/or health‐care workers. ⁷

To the best of our knowledge, there is a lack of data from previously published literature studies about the state of HBeAg among hepatitis B patients in Bahrain. The results of our study revealed that HBeAg‐positive status is prevalent among patients with hepatitis B infection. Almost one‐fifth of the hepatitis B patients in our study had positive HBeAg, indicating their high infectivity and high viral replication. This level is higher that the prevalence reported in other studies. ¹² This is of important consideration because it reflects that the rates of transmission of infection are expected to be high, and better measures should be adapted to reduce the disease infectivity. It also highlights a potential rise in the incidence of cirrhosis and HCC. The average age of HBeAg‐positive patients in our sample was 45 years, which indicates worse outcomes as later seroconversion is linked to complications like liver cirrhosis. ⁷ Patients with cirrhosis, active hepatitis, or older than 40 years of age at the time of HBeAg seroconversion are also at significantly higher risk for HCC development. ¹³

Moreover, less than one‐fifth of hepatitis B patients with positive HBeAg, and only one‐third of patients with negative HBeAg in Bahrain are on antiviral therapy. We did not collect data on time of diagnosis, previous treatment, or length of current treatment, and we cannot comment on the significance of this. A network meta‐analysis suggested that telbivudine treatment followed by tenofovir therapy resulted in higher HBeAg seroconversion rates than other treatments, although its use may be limited by a high resistance rate. ¹⁴ Most patients in our cohort were receiving entecavir, which is a recommended first‐line drug, but long‐term use may reduce HBeAg seroconversion compared with the spontaneous HBeAg seroconversion rate. ¹⁴

In this study, HBeAg were positively correlated with laboratory tests indicative of activity. Patients with positive HBeAg had significantly higher levels of ALT, GGT, and HBc IgM. Although we did not detect a statistically significant association between HBeAg positivity and HBV DNA load, data from previous studies reported that the presence of HBeAg was also associated with high levels of HBV DNA and high rates of infection transmission. ¹ , ⁴ High viral replication and disease activity results in more hepatocellular damage and subsequent high levels of liver enzymes, and this explains our findings that hepatitis B patients with positive HBeAg had higher ALT and GGT levels. ¹⁵ , ¹⁶

While HBeAg's existence is indicative of high viral replication and high infectivity status, it was not associated—in the studied sample—with any increase in the prevalence of hepatitis complications such as cirrhosis, HCC, or the need for transplantation. In contrast to our results, Hou et al. reported in their study of 428 patients with HBV infection that patients with positive HBeAg had higher rates of complications such as liver cirrhosis, hepatic encephalopathy, and liver failure. ¹⁷ The differences encountered in our sample may be related to the different characteristics of the patients recruited.

Of the 262 patients with negative HBeAg, 84.4% had anti‐HBe Ab. The levels of HBeAg decline with the recovery of the acute infection, and seroconversion to HBe Ab takes place. ³ , ⁴ The appearance of HBe Ab often reflects the beginning of remission of active infection. ¹⁸ In our sample, none of the patients with positive HBeAg had HBe Ab detected, indicating that the patients had not entered the recovery stage yet. This is significant at a population level as well because it indicates that these patients would still be infectious for a considerable time, increasing the risk of transmission. Health‐care staff and patient education on the high infectivity of patients with HBV in Bahrain is, therefore, important in preventing further HBV infections. ⁷

In this study, we also evaluated the association of other viruses with HBV infection in Bahrain. The prevalence of HIV among hepatitis B patients in our study was 0.4–1.6%, which is less than what was reported in the meta‐analysis published by Roos et al. in 2010, which reported a prevalence ranging from 4.1 to 26.8%. ¹⁹ Hepatitis C coinfection in our sample ranged from 5.3 to 8.2%, which is also less than what was reported (9–30%). ²⁰ , ²¹ , ²² There was no association between the existence of HBeAg and other viruses such as HCV or HIV.

One of the main strengths of this study is that it is the first study to report the prevalence of HBeAg among hepatitis B patients in Bahrain and to describe correlations with laboratory and clinical profiles. The main limitation, however, is that it was a retrospective record‐review study that lacked the longitudinal follow up to assess the actual impact of HBeAg on a long‐term basis. The study is also based on a single institution, and even though the hospital is the largest one in the country, the findings may not be representative of the whole country as no cases from other governmental or private health facilities were included. This is compounded by the small number of identified cases.

Conclusion

HBeAg positivity is highly prevalent among hepatitis B patients in Bahrain, and it is associated with high liver enzymes and high viral replication. However, patients with positive HBe do not appear to be at a significantly higher risk for hepatitis complications (such as cirrhosis or HCC) or liver transplantation.

Declaration of conflict of interest

The authors declare that there are no competing interests.