[Strategies for hepatitis B virus-infected patients in the immune-tolerant phase: complete therapy at the last mile].

Hepatitis B is mostly a chronic, progressive disease that, if not treated promptly and effectively, can slowly progress to cirrhosis, liver failure, or hepatocellular carcinoma. Therefore, antiviral therapy, i.e., a "complete therapy" strategy, should be started as long as the virus is positive. Immediate antiviral treatment is not recommended for infected patients who are only in the immune-tolerant phase, mainly because of the milder conditions and poor antiviral therapy efficacy, according to antiviral indications in China's Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2022 Version). The relevant issues of why hepatitis B virus infection in the immune-tolerant phase is the last mile of "complete therapy," with an emphasis on the disease's characteristics and antiviral treatment strategies, are discussed here.

[Antiviral therapy for chronic hepatitis B: the imperative to move from scaling-up treatment to full treatment].

Timely and effective antiviral therapy can prevent or delay the progression of the disease to cirrhosis, liver failure, or hepatocellular carcinoma in patients with chronic hepatitis B. Antiviral therapy indications are constantly expanding, and eventually it will be manageable to treat viral positives based on the new understanding of the disease progression and the changes in the definition of abnormal values in liver function tests.

[Clinical efficacy analysis of TMF for the treatment of hyperviremia HBeAg-positive chronic hepatitis B patients with incomplete response to first-line oral antiviral nucleos(t)ide analogues].

Objective: To prospectively explore the treatment strategies for clinical difficulties in patients with hyperviremia HBeAg-positive chronic hepatitis B with incomplete response to first-line nucleos(t)ide analogues (NAs). Methods: Patients with hyperviremia HBeAg-positive chronic hepatitis B were treated with first-line NAs, including entecavir, tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF) for 48 weeks or more. Tenofovir amibufenamide (TMF) or TAF therapy was changed when HBV DNA remained positive and then divided into a TMF group and a TAF group. Clinical efficacy of treatment was evaluated at 24 and 48 weeks, including HBV DNA undetectable rates and virological and serological responses in both patient groups. Results: In the TMF group and the TAF groups, 30 and 26 cases completed 24-week follow-up, while 18 and 12 cases completed 48-week follow-up. There were no statistically significant differences in baseline HBV DNA, HBsAg, and HBeAg levels between the two groups before switching to TMF/TAF therapy (P > 0.05). At 24 weeks of treatment, 19 (19/30, 63.33%) cases in the TMF group had HBV DNA negative conversion, while 14 (14/26, 53.85%) cases in the TAF group had HBV DNA negative conversion (P > 0.05). Among the patients who completed 48 weeks of follow-up, 15 (15/18, 83.33%) cases in the TMF group and 7 (7/12, 58.33%) cases in the TAF group had negative HBV DNA tests (P > 0.05). The changes in HBsAg and HBeAg levels between the two groups of patients at 24 and 48 weeks of treatment were not statistically significant compared to baseline (P > 0.05). Conclusion: TMF is effective in treating patients with hyperviremia HBeAg-positive CHB with an incomplete response to first-line NAs treatment, but there is no significant difference compared to TAF.

[Early-stage clinical features, diagnosis and treatment progress of pregnancy-related liver disease].

Pregnancy-related liver disease is a group of severe diseases that usually resulting in worsening clinical outcome in pregnant women and fetuses. Therefore, diagnosis and treatment at early-stage are essential. This paper reviews the early-stage clinical features, pathogenesis, diagnosis and treatment key points of common pregnancy-related liver diseases such as hyperemesis gravidarum, intrahepatic cholestasis of pregnancy, hemolysis, elevated liver enzymes and low platelet syndrome, and acute fatty liver of pregnancy, in order to help clinicians, improve their understanding of pregnancy-related liver disease.

[Analysis of clinical characteristics of patients with hyperthyroidism combined with liver injury].

Objective: To analyze, explore and evaluate the clinical characteristics, abnormal thyroid function and follow-up of anti-hyperthyroidism treatment mode in patients with hyperthyroidism (commonly abbreviated as HT) combined with liver injury. Methods: The clinical data of patients with hyperthyroidism combined with liver injury were retrospectively analyzed, and then patients were divided into treated and untreated group according to whether they received anti-hyperthyroidism treatment before the consultation. Patients' thyroid and liver function test indicators at the time of treatment were analyzed to determine the main cause of liver injury. The characteristics of liver injury were analyzed in the treatment group. Patients with severe thyroid toxicity and hyperthyroidism combined with liver injury were followed-up with anti-hyperthyroid therapy, mainly low-dose methimazole (MMI) and radioactive iodine therapy to evaluate its efficacy and safety. The comparison between data groups was performed by t-test, rank sum test and χ( 2) test. Results: Among the 43 cases with hyperthyroidism combined with liver injury, 19 were males and 24 were females, aged 49.0 ± 14.6 years-old; 16 cases (16/43, 37.21%) aged 40 to≤60 years- old, and 15 cases (15/43, 34.88%) aged > 60 years-old. There were 22 untreated cases (untreated group, accounting for 51.16%), and 21 treated cases with anti-hyperthyroidism (treatment group, accounting for 48.84%) at the time of consultation. Thyroid function indicators (FT3, FT4, TSH) and liver function indicators (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, γ-glutamyltransferase, total bilirubin) of the two groups were compared, and the difference was not statistically significant (P > 0.05). The order of liver injury from mild to severe in patients with different treatment options were: methimazole (MMI) < propylthiouracil < radioactive iodine

Correlations of Helicobacter pylori with liver function, inflammatory factors and serum levels of FoxP3 and RORγt in patients with hepatitis B cirrhosis.

OBJECTIVE: To investigate the correlations of Helicobacter pylori (HP) with liver function, inflammatory factors and serum levels of forkhead box P3 (FoxP3) and retinoic acid receptor-related orphan receptor gamma-t (RORγt) in patients with hepatitis B cirrhosis (HBC). PATIENTS AND METHODS: A total of 60 HBC patients were divided into HBC group (n=30) and HP-infected HBC group (HP&HBC group, n=30). QRT-PCR was conducted to determine the messenger ribonucleic acid (mRNA) levels of FoxP3 and RORγt in serum samples. ELISA was applied to measure the levels of relevant inflammatory factors. Besides, immunohistochemical staining was conducted to detect positive expressions of FoxP3 and RORγt in liver tissues of patients in the two groups. RESULTS: No significant differences in gender, drinking, smoking, diabetes and age were found between HBC group and HP&HBC group (p>0.05). Globulin and albumin levels were comparable between the two groups (p>0.05). Liver function indexes, including ALT, AST and TBIL were higher in HP&HBC group than those in HBC group (p<0.05). The HBV-DNA level was lower in HBC group in comparison with that in HP&HBC group. The interferon-gamma (IFN-γ) level was remarkably higher in HBC group than that in HP&HBC group (p<0.01), and the levels of interleukin (IL)-6, IL-10, IL-17 and transforming growth factor (TGF)-ß1 were notably lower in HBC group in comparison with those in HP&HBC group (p<0.01). Additionally, the mRNA levels of FoxP3 and RORγt in HBC group were distinctly lower than those in HP&HBC group (p<0.01). The mRNA levels of FoxP3 and RORγt were positively related to those of IL-6, IL-10, IL-17, and TGF-ß1, and negatively associated with IFN-γ level. Immunohistochemical results indicated that positive expression rates of FoxP3 and RORγt in the liver tissues were approximately 50% in HP&HBC group and B. Zhao, Q.-J. Sheng, Y. Qin, X.-L. Wang, H. Zhao, N. Zhaowere 15% in HBC group, and the difference was statistically significant (p<0.05). CONCLUSIONS: Expression levels of FoxP3 and RORγt in serum and liver tissues are elevated in HP-infected HBC patients, and inflammatory factors are correlated with their expressions, suggesting the aggravated liver damage.

[Considerations of using oral nucleos(t)ide analogues to interrupt mother-to-child transmission in HBV carrier pregnant woman with high viral load].

The main transmission route of chronic hepatitis B virus infection is mother-to-child transmission of hepatitis B virus and the main cause of combined immune prophylaxis failure in neonates at the end of pregnancy is high viral load. Moreover, oral administration of nucleos(t)ide analogues (NAs) during the second and third trimesters of pregnancy can significantly reduce or even completely block mother-to-child transmission of HBV. This article focuses on the necessity and feasibility of oral NAs antiviral therapy for HBV carrier pregnant woman with high viral load, and the issues commences at the time of medication and viral load thresholds.

[Clinical characteristics of hepatic flare and efficacy of antiviral therapy in pregnant women with chronic hepatitis B virus infection].

Objective: To analyze the clinical characteristics of hepatic flare and evaluate efficacy of antiviral treatment in pregnant women with chronic HBV infection. Methods: A single-center, open-label, prospective study was conducted, and pregnant women with chronic HBV infection were enrolled. Liver function, HBV serum markers and HBV DNA of pregnant women with chronic HBV infection were reviewed during every 4 to 12 weeks of gestation period. The proportion and clinical characteristics of hepatitis flare during pregnancy were observed. Logistic regression analysis was used to predict hepatic flare in pregnant women with chronic HBV infection. Antiviral therapy with telbivudine (LdT) or tenofovir dipivoxil (TDF) was used to treat hepatic flare during pregnancy. Sequential entecavir (ETV) or TDF was applied after the delivery. Treatment course and drug withdrawal in pregnant women with hepatic flare was the same as those of the general patients with chronic hepatitis B. Liver function, HBV serum markers and HBV DNA were measured in pregnant women with hepatic flare at different time points (4, 12, 24 and 52 weeks). A t-test was used to compare the hepatic flare in pregnant women with and without hepatitis group. HBsAg and HBeAg were used to quantify the receiver operating characteristic (ROC) curve of pregnant women with hepatic flare during pregnancy. Area under the ROC curve was used to calculate the optimal cut-off value corresponding to the maximum sensitivity and specificity of the ROC curve. Results: Of the 220 pregnant women with chronic HBV infection, 55 (25%) had hepatitis flare during pregnancy and received antiviral treatment. Among the 55 women with hepatic flare during gestation, 47 (85.46%) had hepatic flare in the mid-second trimester (12-24 weeks); average peak value of alanine aminotransferase (ALT) was 220.62 U/L, and the average peak value of ALT in 32 cases (58.18%) of pregnant women with hepatic flare was between 2-5 × ULN. HBsAg and HBeAg quantification were significantly lower in pregnant women with hepatic flare during pregnancy than with non-hepatitis (t = -3.745, P < 0.001; t = -2.186, P = 0.030). Multivariate logistic regression analysis showed that pregnant women with HBeAg < 3.065 log10 s/co were 7.576 times more likely to have hepatic flare during pregnancy (95% confidence interval: 3.779-15.190). ALT normalization, undetectable HBV DNA levels, HBeAg loss and HBeAg seroconversion in 55 pregnant women with hepatic flare at 52-week treatment was 100% (55/55), 74.55% (41/55), 47.27% (26/55) and 41.82% (23/55), respectively. HBsAg quantification at 52 weeks was significantly lower than baseline HBsAg quantification (3.32 + 0.37) log(10) IU/ml and (3.95 + 0.40) log(10) IU/ml; t = 8.465, P < 0.001). Conclusion: Hepatic flare often occurs in the second trimester of pregnancy in pregnant women with chronic HBV infection and baseline HBeAg quantification is an independent predictor of hepatic flare. HBeAg seroconversion rate increased at 52 weeks after antiviral therapy.

[The comparison of liver inflammation and fibrosis between chronic HBV and HCV infection].

Objective: To explore the difference of liver inflammation and fibrosis in patients with chronic hepatitis B virus (HBV) infection and chronic hepatitis C virus (HCV) infection, and to investigate the relationship between hepatic pathology and alanine aminotransferase (ALT). Methods: 57 patients with chronic HCV infection and 346 patients with chronic HBV infection who were hospitalized at Shengjing Hospital of China Medical University from January 2012 to September 2016 were enrolled. In chronic HBV infection, including 88 cases whose ALT were more than two times of upper limited of normal (ALT≥2×ULN) and 258 cases whose ALT were less than two times of upper limited of normal (ALT < 2×ULN).All the patients were underwent liver biopsy. Chronic HBV infection (ALT≥2×ULN and ALT < 2×ULN) and chronic HCV infection were compared respectively. Statistical analyses were performed using a Univariate χ²-test and Mann-Whitney U test for comparison. Correlations between variables were analyzed using Spearman's rank correlation. Results: In chronic HBV infection group, 169 cases (48.8%) had inflammation grade≥2 (G≥2), 98 cases (28.3%) had fibrosis stage≥2 (S≥2), 81 cases (23.4%) with G≥2 and S≥2.In the ALT < 2×ULN group, there were 109 cases (42.2%) with G≥2, 62 cases (24%) with S≥2, 49 cases (19%) with G≥2 and S≥2. In the ALT≥2×ULN group, 60 cases (68.2%) with G≥2, 35 cases (39.8%) with S≥2, 31 cases (35.2%) with G≥2 and S≥2. The grade of inflammation and fibrosis have significantly different between ALT≥2×ULN group and ALT < 2×ULN group (χ² = 17.66, χ² = 8.06, P < 0.01). In chronic HCV infection group, 47 cases (82.5%) with G≥2, 20 cases (35.1%) with S≥2, 20 cases (35.1%) with G≥2 and S≥2. ALT had no correlation with inflammation and fibrosis (P > 0.05). The grade of inflammation was significantly different between chronic HCV infection and chronic HBV infection whose ALT < 2×ULN (χ² = 30.19, P < 0.01) but the fibrosis have no difference (χ² = 2.96, P > 0.05). Compared with chronic HBV infection whose ALT≥2×ULN, both inflammation and fibrosis had no significantly different (χ² = 3.65, χ² = 0.32, P > 0.05 respectively). Conclusion: In chronic HBV infection whose ALT < 2×ULN, about 30%-40% liver tissue with significant necroinflammation and /or fibrosis. About 80% chronic HCV infection with significant necroinflammation, and the grade of inflammation has no correlation with ALT. The grade of inflammation has significantly different between chronic HCV infection group and chronic HBV infection group whose ALT < 2×ULN.

[Telbivudine for prevention of perinatal transmission in pregnant women infected with hepatitis B virus in immune-tolerant phase: a study of efficacy and safety of drug withdrawal].

OBJECTIVE: To observe the success rate of telbivudine (LdT) for the prevention of perinatal transmission of hepatitis B virus (HBV) and the incidence of alanine aminotransferase (ALT) elevation during LdT treatment and after LdT withdrawal in HBV-infected pregnant woman with high viremia in immune-tolerant phase and receiving LdT treatment at the end of pregnancy, and to evaluate the efficacy of LdT in the prevention of perinatal transmission and the safety for pregnant women. METHODS: Pregnant women infected with HBV in immune-tolerant phase who had normal ALT levels (≤40 U/L) and high viremia (HBV DNA ≥6 log10 IU/ml) with positive HBeAg were enrolled as subjects. All pregnant women received antiviral treatment with LdT at the end of pregnancy to prevent perinatal transmission of HBV. All infants received standard combined immunoprophylaxis. Failure for prevention of perinatal transmission of HBV was defined as positive HBsAg or HBV DNA in infants 7 months of age (or at one month after the third injection of hepatitis B vaccine). Liver function, HBV DNA, and HBV serological markers were evaluated at baseline, after 1 month of treatment, before childbirth, and 1, 3, and 6 months after drug withdrawal. SPSS 16.0 software was used to analyze the data. Between-group comparison of continuous data was made by t test, and comparison of categorical data was made by chi-square test. RESULTS: One hundred and four pregnant women (treatment group) received oral administration of 600 mg LdT once a day, and 25 pregnant women (observation group) did not receive any antiviral therapy. The success rate for the prevention of perinatal transmission was significantly higher in the treatment group than in the observation group (100% vs 89.47%, χ (2) = 9.862, P = 0.028). There was no significant difference in the incidence of ALT elevation during treatment and within 6 months after drug withdrawal between the treatment group and the observation group (4.81% (5/104) vs 4.00% (1/25), χ (2) = 0.030, P = 1.000). In the treatment group, the mean HBV DNA at baseline was significantly higher than that before childbirth (8.20±0.78 vs 3.98±0.90 log10IU/ml, t = 6.979, P < 0.001). One hundred patients with drug withdrawal had HBV DNA increased to 8.11±0.80 log10 IU/ml at one month after childbirth. CONCLUSION: LdT treatment at the end of pregnancy can effectively reduce the incidence of perinatal transmission of HBV in pregnant women with high viremia in immune-tolerant phase. The immediate drug withdrawal after childbirth is safe for the mother. The incidence of hepatitis is low after drug withdrawal.