| Abstract|| |
Over 350 million people worldwide are infected with hepatitis B virus (HBV), and patients with HBeAg-negative chronic hepatitis B constitute a major proportion of this population. Mutant varieties of HBV resulting from mutations in the precore or core promoter region of the viral genome give rise to HBeAg-negative CHB, and these cases must be differentiated from the inactive carrier state. These patients with HBeAg-negative CHB must be managed judiciously and in certain situations kept under close follow-up instead of rushing to treatment. However, this does not mean advocating adoption of a too conservative approach, allowing many to proceed to irreversible and progressive liver disease. This article provides an overview of the management of HBeAg-negative chronic hepatitis B.
Keywords: Chronic hepatitis B, HBeAg, HBeAg negative, hepatitis B virus
|How to cite this article:|
MA, Fazle Akbar S M. HBeAg negative chronic Hepatitis B: An overview. Hep B Annual 2009;6:131-40
| Introduction|| |
Over 350 million people worldwide are chronically infected with hepatitis B virus (HBV), and globally around 1 million die due to consequences of this infection annually.  Bangladesh belongs to the intermediate prevalence region for HBV infection. Here the lifetime risk of acquiring HBV infection is between 20% and 60%.  Studies from ours as well as other groups have shown that HBV is responsible for 31.25% cases of acute hepatitis,  76.3% cases of chronic hepatitis,  61.15% cases of liver cirrhosis,  and 66% cases of hepatocellular carcinoma  (HCC) in Bangladesh.
There is high prevalence of HBeAg-negative chronic hepatitis B (CHB) in our population. In our series, we found 48.7% CHB patients positive for HBeAg, whereas the remaining 51.3% tested negative. 
We have also observed that the most prevalent HBV genotype in Bangladesh is D (49%) followed by C (38%). In our patients with genotype C, we found more often serum alanine aminotranferase (ALT) and aspartate aminotransferase (AST) elevation than those with genotype D. Also, HBV DNA level is high in patients with genotype C (88%) compared with genotype D (32%). Histologic activity index (HAI) tends to be higher in patients with genotype C infection. 
| Chronic Inactive HBsAg Carrier State|| |
Persistence of HBsAg in blood for more than 6 months is termed as CHB. HBeAg-negative HBV infection may imply chronic inactive carrier state, characterized by HBV DNA < 10 4 copies/mL and normal or near normal hepatic histopathology. In carriers, seroconversion of HBeAg to anti-HBe generally implies reduction of viral activity and improvement in biochemical and histologic parameters.
However, the inactive carrier state must be differentiated from chronic hepatitis (CH) by mutant variety of HBV resulting from mutation in precore or core promoter region of the viral genome giving rise to HBeAg-negative CHB.
Besides, HBeAg seroconversion does not necessarily mean complete cessation of viral replication. It has been observed that over an 8-year follow-up period in a study population of 283 patients, 33% had ALT and HBV DNA elevation and 8% progressed to cirrhosis of the liver. 
The biologic role of HBeAg in the replication of HBV is uncertain. The expression of HBeAg is not essential for viral replication in humans or in animal models. It has been suggested that HBeAg acts as a tolerogen or as a target for immune response. In addition, HBeAg appears to modulate the host immune response.
In one of our studies where we recruited 80 CHB patients, we found that 7.69% patients with HBeAg-positive CHB had minimal chronic hepatitis, 69.23% had mild chronic hepatitis, 19.23% had moderate chronic hepatitis, and severe CH was seen in 3.85%. In case of HBeAg-negative CHB, these figures were 10.71%, 53.57%, 25%, and 10.71%, respectively.  Later we studied a larger sample size and compared not only hepatic necro-inflammation, but also fibrosis between HBeAg-positive and -negative CHB patients. This study included 155 patients of whom 102 were HBeAg-positive and the remaining 55 were negative for HBeAg. It was observed that 20.8% patients with HBeAg-negative CHB had moderate to severe CH. In contrast, moderate to severe CH was seen in 18.6% patients with HBeAg-positive CHB. Significant hepatic fibrosis (ie, HAI-F score ≥ 3) was also more frequent in the HBeAg-negative CHB group (28.3% patients as opposed to 19.6% patients with HBeAg-positive CHB). In both these studies, we observed that patients with HBeAg-negative CHB tend to develop more severe hepatic histologic involvement compared with their HBeAg-positive counterparts.  In one of our more recent works, we studied 42 HBeAg-negative CHB patients with very low HBV DNA count (ie, <10 5 copies/mL) only to discover that even in them, 26.2% patients had significant hepatic necro-inflammation (i.e., HAI-NI score 4-8), whereas significant fibrosis was seen in 19% of the patients.  Similar experience is also shared by studies from Korea,  Turkey,  Egypt,  Greece,  China,  and India. ,,
| Management of HBeAg Negative CHB|| |
It is very important to distinguish chronic inactive HBsAg carriers from HBeAg-negative CHB, as the later group has the potential of developing marked viral reactivation and has less chance of response to antiviral medications.  A recent article from Taiwan reports that the cumulative probability of hepatitis relapse in HBsAg carriers was 26.9% in males and 12.5% in females over a 20-year follow-up period. Moreover, 1.14% patients included in the study progressed to cirrhosis per annum. The sample size in this study was 1241. 
Definitive diagnosis of precore mutation involves sequencing of viral genome.  However, this is more of a research toll with practically no implication in the clinical setting. In an inactive carrier, ALT usually remains normal on serial monitoring with undetectable to low levels (ie, <10 4 copies/mL) of HBV DNA. However, the same may also occur in a patient with HBeAg-negative CHB. HBV DNA is also not a very useful indicator as a Chinese study, involving 165 patients, reported that a single HBV DNA measurement misdiagnoses 45% HBeAg-negative CHB as chronic inactive HBsAg carriers. The study further revealed that even HBV DNA measurement on 3 separate occasions also misdiagnoses 30% cases.  Besides, a study of 196 CHB patients revealed that 10.5% HBeAg-negative CHB patients had HBV DNA < 30,000 copies/mL. 
The only way to distinguish between these 2 entities in a clinical setup is, therefore, performing a liver biopsy. 
The goal of treatment for any CHB patient is to prevent the development of cirrhosis, hepatic failure, and HCC. In HBeAg-negative CHB, response to treatment is said to have been obtained when one becomes negative for HBV DNA by PCR along with normalization of ALT and seroconversion to anti-HBe. The problem, however, is that many HBeAg-negative CHB patients test positive for anti-HBe at baseline and have persistently normal or near normal ALT. Moreover, there is high incidence of relapse in this group of patients, even after HBV DNA becomes undetectable by PCR with treatment, the reason why initiating as well as determining the endpoint of treatment in this group remains extremely difficult. The American Association for the Study of the Liver (AASLD) in its recent CHB guideline advocates treatment of HBeAg-negative CHB patients till HBsAg becomes undetectable.  This is an approach that is perhaps not too appropriate in the Asian setting. The reason for saying so is multifold, including lack of trained specialists, poor socioeconomic condition, lack of patient awareness, poor follow-up, high cost of drugs, and so on.
Besides this, all oral antivirals currently approved for CHB treatment are also associated with variable risk of inducing viral resistance on long-term use. This risk is highest with lamivudine (LAM) and minimal with Entecavir (ETV). This means that there will be high risk of introducing mutant HBV strains.
The emergence of HBV mutant can lead to negotiation of initial treatment. Patients are also at increased risk of developing hepatitis flares and decompensation. Such mutation is initially characterized by viral breakthrough, where there is a >10 log rise in HBV DNA. Viral breakthrough precedes biochemical breakthrough by months. In the latter, there is rise in serum ALT. Such patients also develop cross-resistance to other antivirals, for example, patients resistant to LAM will have cross-resistance to telbivudine (LdT) and vice versa.
Interferon-α (IFN-α) for 48 weeks is associated with 38%-90% response in HBeAg-negative CHB patients as opposed to 0%-39% response in controls;  however, approximately 50% responders relapse posttreatment, some as late as up to 5 years.  The sustained response may, however, be increased with prolonged treatment.  Of these patients, 30%-40% relapsers show sustained response following a second course of IFN-α.  Pegylated IFN for 48 weeks yields better results, and the viral suppression is also better if LAM is added to pegylated IFN, however, the sustained virologic response does not improve with this combination. 
LAM is a nucleoside analog that yields 60%-70% HBV DNA negativity at 1 year in HBeAg-negative CHB,  but 90% of these responders unfortunately relapse posttreatment.  With longer duration of treatment, the response progressively reduces to 73% at 1 year and 34% at 2 years due to the emergence of LAM-resistant strains, usually YMDD mutants,  where addition of adefovir (ADV) or switching over to double dose ETV is usually effective.
ADV on the other hand is a nucleotide analog that leads to HBV DNA negativity in 64% HBeAg-negative CHB patients at 1 year of treatment. ADV is a weaker drug compared with LAM and is unlikely to yield impressive results if the initial HBV DNA load is high. However, in HBeAg-negative CHB patients with low HBV DNA load at baseline, ADV may be a useful first-line option, as it is associated with much lower resistance rate compared with LAM. The addition of ADV to LAM benefits LAM-resistant CHB patients and vice versa, although the latter is much less common.
The drug that is of much discussion these days is a carbocyclic analog called Entecavir. It is much superior to LAM or ADV and is effective in LAM-resistant cases.  At 48 weeks, ETV yields HBV DNA negativity in 90% HBeAg-negative CHB patients as compared with 78% with LAM. 
LdT, an l-nucleoside analog, is a newer addition to the growing list of oral antivirals for CHB and at 1 and 2 years shows much better response to LAM in HBeAg-negative CHB. However, these relatively newer drugs, such as ETV or LdT are yet to be time tested for long-term outcome.
Patients with HBeAg-negative CHB must, therefore, be managed judiciously and in certain situations kept under close follow-up instead of rushing to treatment. However, this does not mean advocating adoption of a too conservative approach, allowing many to proceed to irreversible and progressive liver disease [Figure 1]. 
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Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka
Source of Support: None, Conflict of Interest: None