The effect of patients with chronic hepatitis B HBeAg（+）with poor response to treatment by converting to sequential treatment with tenofovir dipivoxil

Zhi-Xiong Liao , Ya-Hui Luo , Liang-Bin Cheng

1. Department of Internal Medicine, Hanchuan Traditional Chinese Medicine Hospital, Hubei, Xiaogan 431600, Hubei

2. Department of Pediatrics, Hanchuan People's Hospital, Hubei, Xiaogan 431600, Hubei

3. Department of Hepatology, Hubei Traditional Chinese Hospital, Wuhan 430061, Hubei

Keywords:

ABSTRACT

1. Introduction

In China, Hepatitis B virus （HBV） infection is the main cause of chronic liver failure [1]. Therefore, “Guidelines for the Diagnosis and Treatment of Liver Failure （2012 Edition）” recommends the addition of antiviral drugs on the basis of comprehensive medical treatment [2]. Chronic hepatitis B is one of the high-incidence diseases in China, and HVB infection seriously threatens people's health [3]. In the hepatitis B prevention and treatment guidelines in most parts of the world, for patients with chronic hepatitis B （CHB） positive for e-antigen （HBeAg）, HBeAg serodiversion was used as an endpoint [4-5]. At present, clinically, tenofovir disoproxil fumarate fumarate tablets are used to treat drugs [6], but some patients have a poor response to it [7]. There are still studies showing that switching to tenofovir disoproxil sequential treatment can improve the eきcacy [8]. In order to explore the eあect of poor treatment response of patients with hepatitis B HBeAg （+） who switched to sequential treatment with tenofovir disoproxil, the research group selected 90 patients with chronic hepatitis B HBeAg （+） in our hospital as the research object and started a comparative analysis. The results are reported below.

2. Materials and methods

2.1.Subject

From December 2016 to December 2018, a retrospective study was conducted on 90 patients with chronic hepatitis B HBeAg （+）admitted to the internal medicine department of Hanchuan Hospital of traditional Chinese medicine in Hubei Province. The enrolled patients were those who were enrolled continuously during the study period. The study was approved by the medical ethics committee of Hanchuan Hospital of traditional Chinese medicine in Hubei Province （approval number: Yilun 2016101301）.

（1） diagnostic criteria: Hp-hbv was diagnosed according to the diagnostic criteria specified in the guideline for the prevention and treatment of chronic hepatitis B （2019）, and interferon or pegylated interferon was used continuously for more than 24 weeks, and one of the following conditions was met: HBeAg titer ＞ 500 coi, or HBV-DNA load ＞ 105 IU / ml, or HBV DNA load decreased ＜ 2log10 IU / ml, or IFN could not be tolerated；HBsAg, anti HBC were all positive, HBeAg was positive or negative [9].

（2） Inclusion criteria: patients did not receive systematic treatment before the onset of the disease；the case information was complete；patients knew and agreed to the research content and treatment plan.

（3） Exclusion criteria: hepatitis A, C, D, E virus infection and human immunodeficiency virus （HIV） Co infection, decompensated cirrhosis and liver cancer；severe organ dysfunction；patients with tumor, blood system, immune system and mental disease；estimated survival time ＜ 1 year；diあerent from the requirements of this test, or unable to cooperate with the treatment, or unable to follow up on time.

There was no significant diあerence in gender, genotype, age and course of disease between the two groups （P ＞ 0.05）. Show in Table 1 for details.

2.2.Grouping and treatment method

according to the diあerent treatment plan of the patients, they are divided into two groups: extension group and transfer group. Each group has 45 patients. The treatment method is as follows.

（1） Extension group: patients in this group were treated with tenofovir fumarate dipivoxil tablets. Take tenofovir dipivoxil fumarate tablets （TDF, produced in Gilead company, South Africa） orally once a day for 48 weeks.

（2） Diversion group: the patients in this group were first treated with tenofovir fumarate dipivoxil tablets, no significant improvement was found after 24 weeks, and if there was a virological rebound or breakthrough in the treatment process, regardless of whether genotypic resistance was detected, they were all transferred to transtenofovir dipivoxil.

2.3. Investigation content

（1） Serology and genotyping: HBsAg, HBeAg and HBeAg were measured （ELISA was used, and the instruments and reagents were from American abott company）. Extraction of DNA from 100 UL serum and determination of HBV DNA nucleotide sequence. PCR detection of HBV DNA reverse transcriptase （nucleotide 130-1161） was carried out in two parts. The first generation and the second generation PCR of the first reverse transcriptase region were detected under diあerent conditions by using the primers BGF1 （sense chain；5 '- ctgtggagaaggctggcattct-3'）, bgr2（antisense chain；5 '- ggagatagcccatt-gtg-3'）, respectively. The detection conditions were 4 min pre denaturation and 35 cycles amplification:94c, 1 min 55C, 2 min；72C, 3 The reaction was extended at 72C for 7 min. Reverse transcriptase region sequencing was performed at the beginning of TDF treatment and when virological breakthrough occurred during the treatment [10-11].

Table 1 Basic information of two groups [n （%）/]

Table 2 Comparison of HBeAg and HBV-DNA content between the two groups before and after treatment （±s）

Table 2 Comparison of HBeAg and HBV-DNA content between the two groups before and after treatment （±s）

IndexGroupsTimeComparison BeforeOne monthSix months Twelve monthsFP HBeAg （PEI/ml） Extension Group（n=45）1.74±0.231.50±0.201.21±0.250.90±0.17128.9450.000 Diversion Group（n=45）1.70±0.251.52±0.241.01±0.170.69±0.10243.3960.000 Comparation：t（P）0.635（0.557） 0.349（0.719）（0.000）（0.000）HBV-DNA（IU/ml） Extension Group（n=45）8.63±1.247.43±1.065.25±1.144.37±1.26124.0960.000 Diversion Group（n=45）8.60±1.317.47±1.104.60±1.093.26±0.94220.7440.000 Comparation：t（P）0.286（0.859） 0.496（0.772）（0.000）（0.000）

Table 3 Comparison of liver function indexes between the two groups before and after treatment （±s）

Table 3 Comparison of liver function indexes between the two groups before and after treatment （±s）

IndexGroupsTimeComparation Before One monthSix monthsTwelve monthsFP TBIL（umol/L） Extension Group（n=45） 195.23±20.64 205.60±22.47216.32±24.37234.72±27.5612.8540.000 Diversion Group（n=45） 195.83±20.29 206.03±22.98790.63±86.231035.72±92.4418.2690.000 Comparation：t（P） 0.854（0.336） 0.479（0.690） 12.854（0.000） 16.963（0.000）TC（mmol/L） Extension Group（n=45）2.37±0.452.39±0.412.42±0.442.45±0.490.5700.662 Diversion Group（n=45）2.36±0.412.42±0.402.43±0.452.47±0.400.6490.418 Comparation：t（P） 0.526（0.447） 0.329（0.864） 0.927（0.115） 0.346（0.668）INR ratioExtension Group（n=45）4.05±0.742.96±0.702.84±0.662.70±0.3935.2150.000 Diversion Group（n=45）4.03±0.712.95±0.742.60±0.292.35±0.2369.6550.000 Comparation：t（P） 0.659（0.447） 0.854（0.296） 4.987（0.000） 23.338（0.000）

Table 4 Comparison of serological response and biochemical response between the two groups before and after treatment n （%）

（2） Liver function: before treatment and 1 month, 6 months and 12 months after treatment, blood samples were collected to detect the serum biochemical index and coagulation index value （the reagent was purchased from Roche company） by ELISA, and the serum HBV-DNA value was detected by real-time fluorescent quantitative PCR （the reagent was purchased from Shanghai Fuxing company）. Serum ALT, TBIL, ALB, TC, INR and HBVDNA load were compared between the two groups. HBV-DNA detection value was lower than the detection lower limit （HBVDNA ＜ 5x102 U / ml） and HBV-DNA turned negative [12].

（3） Adverse reactions: the patients in the two groups were monitored for gastrointestinal symptoms, nausea / asthenia and rash before and after treatment. There was no drug discontinuation due to adverse reactions in the experimental group.

2.4 Statistical analysis

use spss20.0 for statistical analysis of the database. The measurement data （content of each index） can be subject to follow-up inspection only when it is subject to normal distribution through KS inspection. If it is not subject to normal distribution, it can be subject to normal distribution through diversion. The measurement data were described by （mean ± standard deviation）, the comparison between groups was performed by two independent samples t-test, and the four time points before and after treatment （before treatment, 1 month of extension / diversion, 6 months of extension / diversion, 12 months of extension / diversion） were compared by F-test. The counting data were described by n （%）, and the comparison between groups was performed by chi square test. Test level 0.05, bilateral probability.

3. Result

3.1 Comparison of HBeAg and HBV-DNA content between the two groups before and after treatment

The content of HBeAg and HBV-DNA in the two groups before and after treatment was significantly diあerent （P ＜ 0.05）between the two groups after 6 and 12 months, and the content of HBeAg and HBV-DNA in the transfer group was significantly lower than that in the extension group. At diあerent time points, the content of HBeAg and HBV-DNA decreased significantly with the time of migration. Show in Table 2 for details.

3.2 Comparison of liver function indexes between the two groups before and after treatment

The difference of TBIL content and INR ratio between the two groups was significant （P ＜ 0.05） after 6 and 12 months, and the TBIL content and INR ratio in the transfer group were significantly lower than those in the extension group. At diあerent time points, TBIL content and INR ratio decreased significantly with time migration. Show in Table 3 for details.

3.3 Comparison of serological response and biochemical response between the two groups before and after treatment

There were significant differences in the number of HBeAg serodiversion and ALT normalization between the two groups before and after treatment （P ＜ 0.05）. At different time points, the number of HBeAg serodiversion and ALT normalization increased significantly with time. See Table 4 for details.

Table 5 Comparison of adverse reactions between the two groups n （%）

3.4 Comparison of adverse reactions between the two groups

The incidence of adverse reactions in the extension group （17 cases, 37.78%） was higher than that in the transfer group （8 cases, 17.78%）. The difference was statistically significant （X2 = 4.486, P ＜ 0.05）. The distribution of specific complications is shown in Table 5.

4. Discussion

With the development of society, hepatitis B is a global infectious disease [13], which is one of the common infectious diseases in China [14]. In the later stage of hepatitis B, serious complications will gradually occur [15]. At present, cirrhosis, liver cancer and other complications have seriously threatened people's life and health [16]. Hepatitis B is mainly caused by HBV infection [17]. At present, the common types of hepatitis B are CHB, hepatitis B cirrhosis, carriers and occult CHB, among which CHB is the most common [18]. CHB is a kind of disease caused by the infection of hepatitis virus. Its mechanism is that the virus damages the patient's hepatocytes by mediating T cells [19]. This kind of virus has many ways of transmission and is highly infectious. Because of its long treatment course, it increases the diきculty of clinical treatment [20]. At present, drug therapy is mainly used in clinic, and antiviral therapy is carried out by using interferon and nucleoside analogues. The former is injected with drugs, the patients have poor clinical compliance and many adverse reactions [21-22]. According to relevant studies, nucleoside analogues, such as tenofovir （TDF）, can eあectively reduce the incidence of adverse reactions in the treatment process [23], and have better clinical eきcacy than interferon.

The results of this study showed that there were significant differences in HBeAg content, HBV-DNA content, TBIL content and INR ratio between the two groups after 6 and 12 months. The HBeAg content, HBV-DNA content, TBIL content and INR ratio in the transfer group were significantly lower than those in the extension group. The HBeAg content, HBV-DNA content, TBIL content and INR ratio decreased significantly with time migration. Tenofovir can regulate the immune function of the body, improve the cytotoxic eあect of NK cells and T cells, promote or induce the expression of the main histocompatibility complex antigen of the cell epidermis, enhance the phagocytosis of the phagocyte, and reduce the damage to the liver function. At the same time, tenofovir is easy to be phosphorylated by cell kinases to produce tenofovir diphosphate with pharmacological activity, which then competes with 5 '- triphosphate deoxyadenylate to enter the HBV-DNA chain, terminating the elongation of the DNA chain and inhibiting the replication of HBV [24]. Therefore, it can effectively reduce the damage to the liver and eあectively inhibit the replication of the virus in patients with chronic hepatitis B HBeAg （+） [25].

At the same time, the results of this study showed that the number of HBeAg serodiversion and ALT normalization was significantly different between the two groups after 1 month, 6 months and 12 months. The number of HBeAg serodiversion and ALT normalization in the transfer group was significantly higher than that in the extension group. With time migration, the number of HBeAg serodiversion and ALT normalization in the two groups increased significantly. The total number of gastrointestinal symptoms, nausea/ fatigue and adverse reactions in the transfer group were significantly lower than those in the extension group. Because TDF has a more significant role in improving the liver function, so the liver function is easy to recover, thus avoiding the abnormal transcription and translation of enzymes, reducing the probability of gastrointestinal complications, and not prone to allergic symptoms such as rash [26-28]. The treatment of chronic hepatitis B HBeAg（+） patients with poor response was transferred to tenofovir dipivoxil sequential treatment, which eあectively improved the treatment eあect of the patients, and then eあectively alleviated the nausea / fatigue and other symptoms of the patients.

To sum up, the sequential treatment of tenofovir dipivoxil can not only improve the treatment eあect, improve the quality of life of patients, but also effectively reduce the incidence of adverse reactions, which is more conducive to the rehabilitation of patients.