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Factors Affecting the Progression of Chronic Hepatitis B Virus Infection


Immune tolerance Immune clearance Low replication phase

Reactivation phase

HBeAg (

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HBV DNA

Factors Affecting the Progression of Chronic Hepatitis B Virus Infection

HBeAg (- anti-HBe ( (Precore/core promoter variant)

2000 IU/mL

< 2000 IU/mL

8 11

2 x 10 - 2 x 10

IU/mL 200,000 - 2 x 10 9 IU/mL

ALT

Chronic hepatitis: None/mild

Chronic hepatitis: moderate/severe Chronic hepatitis: None/mild

Chronic hepatitis: moderate/severe

Cirrhosis Inactive Cirrhosis Cirrhosis

Chronic hepatitis B HBeAg ( )

Healthy carrier

Chronic hepatitis B HBeAg (-)

Figure 1.6: Stages of hepatitis B virus infection [94]

Most patients in the immune clearance phase are usually asymptomatic but have moderate to high elevations in ALT. This is why it is called HBeAg-positive chronic hepatitis B. Clinical significance can be highlighted by acute hepatitis flares with ALT elevations 5 times the ULN. Elevated ALT and acute hepatitis flares are considered to be the result of an immune response to HLA-I antigens, a cell-mediated immune response against HBV antigens, and its apoptosis. The reason for acute hepatitis flares is unclear but is likely explained by changes in immune control of HBV replication. Several studies have shown that acute viral hepatitis flares are often preceded by rapid elevations in HBV-DNA and enhanced T-cell responses to HBeAg and HBcAg. The changes in HBV-DNA and ALT levels during this acute flare are similar to those seen in acute flares following corticosteroid or anticancer chemotherapy. The histological lesions of lobular hepatitis are similar to those of acute hepatitis with bridging necrosis, which is often seen during flares. Anti-HBc IgM may also be present in some patients during the acute flare phase of hepatitis but at lower levels than in acute hepatitis [94].

The immune clearance phase has variable duration and often lasts for many years until HBeAg seroconversion. Seroconversion



usually begins with elevated ALT and decreased HBV-DNA, followed by a decrease in serum HBV-DNA to levels only detectable by PCR (<2 x 10 3-4 IU/ml), normal ALT, and decreased liver necrosis. However, ALT and HBV-DNA abnormalities >2 x 10 4 IU/ml persist at the time of HBeAg seroconversion in approximately 5% of patients. These patients progress directly from HBeAg-positive chronic hepatitis B to HBeAg-negative chronic hepatitis B [94].

- Inactive or residual phase

Inhibition of HBV replication reduces the inflammatory activity (reduced HBV-DNA, normalized ALT, and decreased necroinflammation) that occurs after seroconversion from HBeAg-positive to anti-HBe-positive. Most seroconverted patients remain HBeAg-negative and anti-HBe-positive for life.

- Reactivation phase

After a certain period of time, some patients experience a reactivation phase with increased serum HBV-DNA load, and PC/BCP mutations appear. PC mutations create a stop codon in the HBV genome and stop HBeAg synthesis, while BCP mutations directly affect the transcription of the code to synthesize HBeAg. These mutations can occur alone or in combination, but HBV continues to proliferate despite HBeAg negativity, creating a group of HBeAg-negative chronic hepatitis B. The progression of HBeAg-negative chronic hepatitis B is characterized by continued increase and fluctuation of ALT, the appearance of clinical symptoms, and increasing liver cell damage, which can easily lead to cirrhosis.

1.5.2. Factors affecting the progression of chronic hepatitis B virus infection

- Factors caused by hepatitis B virus

+ Serum HBV-DNA load

Serum HBV-DNA load testing plays an important role in the diagnosis of chronic hepatitis B. HBV-DNA load is a direct marker of viral replication, and is an accurate test to assess the existence and replication of HBV, especially when there is a PC mutation of HBV that makes HBeAg negative but HBV is still active. Serum HBV-DNA level is one of the factors predicting the progression of liver damage as well as response to treatment.


Hepatitis B virus

HBV-DNA (>2 x 10 3-4 IU/ml)

Other factors

Genotype C, D

BCP A1762T mutation

G1764A, Pre-S

Host

- Drink alcohol

- Smoke

-Exposure to aflatoxin

-Co-infection with HCV, HDV, HIV

- Age: > 40 years old

- Gender: Male > female

- Immune status

- Family history: HCC,

cirrhosis

Progressive liver disease

Cirrhosis and or cancer

liver cancer

Figure 1.7: Factors influencing the progression of chronic hepatitis B [93] Much evidence supports the association between high HBV replication capacity with hepatitis, the risk of cirrhosis and HCC. HBV replication determined by the detection of serum HBV-DNA (10 5 -10 6 copies/ml) or HBeAg positivity increases the progression of chronic hepatitis B to cirrhosis. Delayed HBeAg seroconversion (patients over 40 years old) and HBeAg seroconversion after spontaneous HBeAg conversion indicate prolonged viral replication and necroinflammation, increasing the risk of cirrhosis. In European studies, the study

A 25-year longitudinal study in Italian patients with HBeAg-positive chronic hepatitis B at diagnosis showed a 33-fold increased risk of liver-related death in patients who remained HBeAg positive and 38-fold increased risk in patients who were HBeAg negative or had HBeAg conversion to healthy carriers [54]. Other studies have shown that patients with compensated cirrhosis, HBeAg positive and/or HBV-DNA detected in serum, are at high risk of progression to decompensation and death [55].



In Asia, a study of 11,893 male patients in Taiwan found a 10-fold increased risk of HCC in patients who were HBsAg-positive alone and a 60-fold increased risk for those who were HBsAg-positive and HBeAg-positive at diagnosis compared with those who were negative for both tests [167]. The increased risk of HCC in HBeAg-positive patients remained significant regardless of serum ALT levels and cirrhosis status [173]. A population-based cohort study of more than 3,500 untreated HBsAg carriers (45 years of age at selection, 85% HBeAg-negative, 94% normal ALT) in Taiwan found that the risk of cirrhosis and HCC increased significantly with baseline HBV-DNA load detected by PCR [35],[66]. The relative risk of cirrhosis was 2.5; 5.6 and 6.5 when the initial HBV-DNA load was similar.

corresponding to or greater than 10 4 , 10 5 and 10 6 copies/ml [66]. The risk of HCC is significantly increased.

at 10 4 copies/ml and highest for patients with high baseline HBV-DNA load (>10 6 copies/ml) with corresponding hazard ratios of 2.3 and 6.1 [35]. HBV-DNA concentration remained an independent predictor of cirrhosis or HCC after adjusting for other risk factors such as age, sex, alcohol consumption, smoking, HBeAg status and serum ALT [66]. Prospective cohort study of 2763

In Chinese adults with HBsAg positivity, high baseline HBV-DNA load (10 5 copies/ml) was found to be associated with increased mortality from HCC and chronic liver disease over an 11-year period [38].

+ Genotype of hepatitis B virus

Genotype is a factor that not only predicts clinical progression but is also related to the response to IFN-α treatment. In a study comparing genotypes B and C, ALT levels were found to be higher in genotype C than in genotype B [164]. In a study conducted in China, the authors found that the immune clearance phase in genotype C was longer than in genotype B, the level of viral replication was higher, and histological damage was also higher. The possible relationships between genotypes B, C, and follicular helper T (Tfh) cells in patients with chronic hepatitis B were evaluated. Tfh cells play an important role in transmitting signals that influence cell division, activate B cells, and regulate humoral immune responses. In addition



Tfh cells secrete cytotoxic T cells, IL21 to maintain long-term, effective, and antiviral immunity in chronic infection. High HBV-DNA and ALT loads in patients with genotype C infection may be associated with reduced peripheral blood Tfh cell concentrations, which would result in reduced IL21 when compared with genotype B [165]. Most studies compared disease manifestations in patients with genotype C infection with genotype B. The results showed that patients with genotype C infection had higher HBeAg seroconversion in the elderly and higher HBeAg positivity in the elderly than genotype B, genotype C was associated with an increased risk of hepatic inflammatory response, hepatitis flare, and cirrhosis [33],[74].

Several cross-sectional studies have been conducted to evaluate the association between genotypes B and C with HCC. In most studies, genotype C was associated with an increased risk of HCC, with genotype C being significantly associated with HCC in young individuals (<50 years) and genotype B being associated with HCC mainly in those over 60 years [89]. In another cross-sectional study, the risk of HCC did not differ between genotypes B and C, but the risk of HCC in genotype C was higher in younger patients [141]. BCP mutations were identified as independently associated with HCC and were more common in genotype C. The two largest studies, including 426 and 4841 patients followed for an average of 4.8–14 years, found a significantly increased risk of HCC in genotype C compared with genotype B.

+ Mutation in the pre-core/basal core promoter gene region

The PC/BCP gene region is located on the C gene structure, containing genetic information encoding HBcAg and HBeAg. The BCP region is located in front of the PC region, and these two regions are related to each other in the process of copying genetic information and replication of HBV. In 1989, the authors discovered that Greek and Italian patients infected with HBV progressed rapidly to chronic hepatitis B virus. Testing of these patients showed negative HBeAg, positive anti-HBe but rapid HBV replication and positive HBV-DNA. When using PCR technique to amplify the PC region, a mutation was detected at nucleotide 1896 (PC G1896A) [27].

The mutation in the BCP region occurs at nucleotide position 1762, adenine (A) is replaced by thymidine (T) (BCP A1762T) and at nucleotide 1764 guanosine (G) is replaced



by adenine (BCP G1764A). The resulting BCP mutation prevents HBeAg synthesis but HBV still replicates.

Chronic hepatitis due to PC/BCP mutant HBV occurs worldwide but the prevalence is not fully documented. The difference in the prevalence of PC mutant HBV in different geographical areas is related to genotype. The mutation that creates the termination codon is found only in patients infected with genotypes that carry thymidine at nucleotide position 1858. Nucleotide 1896 has a base pair structure with nucleotide 1858 in genotypes B, D, E, G and some sequences of genotype C contain thymidine. Therefore, the G1896A nucleotide mutation stabilizes the ring structure. PC gene-stopping mutations are rarely detected in genotypes A, F, and some genotype C sequences due to the presence of cytidine (C) at nucleotide 1858. Patients infected with genotype C select for PC mutations more often in Southeast Asia than in Taiwan but not in Japan, while genotype F is found in Central America [75]. BCP mutations at nucleotides 1762 and 1764 result in reduced translation of pre-C/CmRNA, reducing HBeAg synthesis. BCP mutations are common in genotypes A and C, with low rates in genotypes B and D. The presence of PC/BCP mutations may play an important role in causing continued liver cell destruction after HBeAg conversion.

- Human body elements

Human factors associated with the progression of chronic hepatitis B to cirrhosis and complications include older age, male sex, and presence of liver disease. Other factors that may influence this include a family history of HCC and cirrhosis. Men are at higher risk of HCC than women, especially those over 45 years of age. Some studies have shown that Asian patients over 40 years of age have a higher risk of cirrhosis and HCC than younger patients [35],[66]. The risk of HCC is higher in those with a family history of HCC, suggesting a role for genetic susceptibility [174].

- Other factors

Coinfection with HCV, HIV and HDV, alcohol consumption, aflatoxin exposure and smoking are factors that may influence the progression of chronic HBV infection especially coinfection with HCV, HDV and HIV.


1.6. Factors affecting the effectiveness of treatment of chronic hepatitis B virus

1.6.1. Treatment goals

The goal of treatment for chronic hepatitis B is to improve quality of life and save lives by preventing disease progression to cirrhosis, HCC, and death [53],[95],[102]. These include:

- Normal ALT

- Decrease or loss of HBV-DNA

- Seroconversion in HBeAg positive patients

- Improve the histological condition of liver cells

- HBsAg seroconversion

This goal can be achieved if HBV replication is sustainably inhibited. Sustained inhibition of HBV replication improves the histological status of liver cells, reducing the risk of cirrhosis and HCC, especially in patients without cirrhosis. However, in chronic hepatitis B, HBV cannot be completely eliminated due to the persistent existence of cccDNA in infected liver cells, which explains the outbreak of HBV. Furthermore, the HBV genome integrates into the genome of liver cells, creating favorable conditions for tumorigenesis and HCC [53]. The challenge for physicians at the end of treatment is the HBeAg, HBsAg seroconversion and limiting the emergence of drug-resistant HBV strains.

1.6.2. Treatment indications

Indications for antiviral treatment are similar for HBeAg-positive and HBeAg-negative chronic hepatitis B [53]. Indications are based on three factors:

- Serum HBV-DNA load

- Serum ALT concentration

- Severity of liver disease

Patients should be considered for treatment when HBV-DNA load is above 2000 IU/ml, ALT levels are above the normal limit, and disease severity on liver biopsy (or non-invasive testing) shows moderate to severe necrosis. In these cases,



Patients who meet HBV-DNA and histology criteria can be treated immediately even if ALT is normal. Treatment decisions should be based on age, health status, family history of HCC or cirrhosis, and extrahepatic manifestations.

Specific indications:

- HBsAg positive for ≥ 6 months

- HBV-DNA load 2 x 10 4 IU/ml for HBeAg positive patients. HBV-DNA load 2 x 10 3 - 10 4 IU/ml for HBeAg negative patients.

- ALT concentration increased ≥ 2 ULN.

If ALT increases 1-2 ULN, HBV-DNA load is high and the patient is ≥40 years old or has a family history of HCC, a liver biopsy or Fibroscan measurement will be indicated to show moderate or severe necroinflammatory reaction and cirrhosis (stage F2 or higher according to the Metavir scale), antiviral treatment is indicated [102],[53].

1.6.3. Antiviral treatment strategy

Currently, there are 2 treatment strategies for both HBeAg-positive and HBeAg-negative chronic hepatitis B virus infection: [53],[95],[102],:

- Long-term treatment with Interferon (IFN) or Pegylated Interferon (PegIFN) especially PegIFN.

Treatment time: 12 months

- Long-term treatment with NA antiviral drugs: LMV, ADV, ETV, TDF and telbivudine (LdT). Of which, ETV and TDF are drugs with high genetic resistance barriers and low resistance rates, so they are chosen as the first drugs in the treatment of chronic hepatitis B with current NA drugs.

Treatment duration: Patients with HBeAg-positive chronic hepatitis B are treated until HBeAg seroconversion occurs after 12 months and patients with HBeAg-negative chronic hepatitis B are treated until HBsAg seroconversion occurs.

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