| Background Worldwide, chronic hepatitis B virus (HBV) infection affects approximately 400 million people, which usually runs a variable course lasting for decades and often the entire life,with ranging from asymptomatic carrier state to cirrhosis,liver failure,and hepatocellular carcinoma (HCC). In the Asia-Pacific region, the mortality is estimated to be more than 200,000 people per year from cirrhosis and more than 300,000 per year from HCC. Antiviral therapy has been shown to be effective to slow down disease progression in these patients. International guidelines have recommended initiating antiviral treatment mainly based on the assessment of serum alanine aminotransferase (ALT) and HBV DNA levels,or liver histology. However, by using ALT and HBV DNA levels without resorting to liver biopsy to define inactive carrier state, we may miss histologically significant disease in a proportion of 40.2% to 65.5% in hepatitis B e antigen positive (HBeAg-positive) patients and 13.8% to 63.9% in hepatitis B e antigen negative (HBeAg-negative) patients. Meanwhile, for chronic hepatitis B (CHB) patients with persistently normal ALT (PNALT), 25.4% of them had significant necroinflammation and/or fibrosis, and almost 10% had established cirrhosis, even though using the new upper limits of normal (ULN) values for ALT (30 IU/L for men and 19 IU/L for women). In that case,antiviral treatment is recommended for a proportion of CHB patients with PNALT. Assessment of liver disease state remains a crucial criterion for making decisions regarding initiation of antivirals. But in the clinical, most chronic hepatitis B patients would not accept liver biopsy, so to evaluate liver disease state and antiviral treatment indications with non-invasive evaluation is necessary.Objectives To describe the characristics of liver histology of chronic hepatitis B patients with PNALT. To explore the non-invasive evaluation that can assess the liver disease state and antiviral treatment indictions in CHB patients with PNALT.Methods This is a retrospective study. Consecutive CHB patients who were regularly attending out-patient service in Infectious disease department of Hospital of Guangxi Medical University from January 2002 to January 2015,were potential study population. Patients were included if they fulfilled the following inclusion criteria:(1) HBsAg positive for at least 6 months,(2) ALT< 1 x ULN,(3) HBV DNA positive, (4) aged 16 to 65 years. The exclusion criteria were as follows:(1) co-infection with HIV, HCV and HDV, (2) with less than three ALT determinations at least 2 months apart in the previous 1 year’s follow-up, (3) ultrasonic revealed liver cirrhosis, (4) antiviral treatment naive or have been off-treatment before liver biopsy. All enrolled patients underwent liver biopsy and had a complete physical examination and laboratory tests. All patients signed informed consent form before enrolled in the study.Results1.With an average age of 39.4 years, the biggest age 64 years, minimum age 16. Male,144 cases (67%),71 cases (33%) women.92 cases (42.8%) with a clear family history, family history not sure of 88 cases (40.9%), with no family history of 35 cases (16.3%). HBeAg positive for 82 cases (38.1%), HBeAg negative 133 cases (61.9%). ALT mean 28.08±7.87 U/L, AST mean 27.86± 6.68 U/L and HBV DNA mean 4.99±1.77 log10.2.215 cases of patients with liver tissue inflammation activity (mean 1.47± 0.847, the degree of fibrosis mean 1.33±1.207. patients with G< 2 and S<2 were 93 cases (43.3%), patients with G≥2 and S< 2 were 32 cases (14.8%), patients with G< 2 and S≥2 were 24 cases (11.2%), patients with G≥2 and S ≥2 were 66 cases (30.7%).3.89.8%(193/215) of patients with PNALT and positive HBV DNA with HBV infection existed liver inflamation, which were 95 cases (44.2%) with G1,74 cases (34.4%) with G2, and 22 cases (10.2%) with G3,2 cases (0.9%) with G4. 67.9%(146/215) of patients existed liver fibrosis, which were 56 cases (26%) with S1,51 cases (23.7%) with S2,27 cases (12.6%) with S3,12 cases (5.6%) with S4. There are 93 cases (43.3%) with mild liver tissue damage (G<2 and S <2),122 cases (56.7%) apparent severe liver tissue damage (G≥2 or S≥2).4. According to age,215 cases were divided into three groups:<30 years old, 30～39 years old,≥40 years old. Patients with G≥2 respectively in three groups:14 cases (35.9%),27 cases (42.86%),57 cases (50.44%), showing no statistically significant difference between the three groups (P> 0.05). patients with S≥2 respectively in three groups:10 cases (25.64%),24 cases (38.1%),56 cases (49.56%), showing statistically significant difference between the three groups (P=0.026). Severe liver tissue damage(G≥2 or S≥2) in the distribution of three groups:17 cases (43.59%),30 cases (47.62%),75 cases (66.37%), showing statistically significant difference between the three groups (P=0.01).5. According to the degree of HBV DNA,215 patients were divided into three groups:<3 log 10,3～6 log 10,≥61og10. patients with G≥2 respectively:18 cases (69.23%),55 cases (44.35%)and 25 cases (38.46%) (P=0.025). patients with S≥2 respectively:17 cases (65.38%),53 cases (42.74%) and 20 cases (30.77%) (P=0.004). Severe liver damage in three groups, respectively for 20 cases (76.92%),70 cases (56.45%),32 cases (49.23%) (P=0.047).6.Liver inflamation in patients with HBeAg positive were lower than those with HBeAg negative (34.15% vs 52.63%, P<0.05). The liver fibrosis stage in group of HBeAg negative were severer than group of HBeAg positive (49.62% vs 29.27%, P<0.05). Liver tissue damage in patients with HBeAg positive were lower than those with HBeAg negative (45.12% vs 63.91%, P<0.05).7. In patients those younger than 30, liver tissue damage in patients with family history, HBeAg negative, HBV DNA<41og10 were more severe.In patients those 30～39 years old, liver tissue damage in patients with family history, HBeAg negative, HBV DNA<41og10 were more severe. In patients those≥40 years old, with or without family history, HBeAg negative or positive, more than 60% patients with severe liver tissue damage.8. There are 11 cases with PNALT accepted twice liver biopsy, the average follow-up of 2.8 years,8 cases present HBV DNA negative in baseline when detected with homemade reagent for detection, there are 5 cases have progress in liver histology after 2.8 years on average, and there are 7 cases present positve HBV DNA when detected with high sensitive reagent. And 3 patients with positive HBV DNA in baseline all heve progress in liver histology after an average of 2.8 years.conclusion1. Most of chronic HBV infection with PNALT have liver histology change, 56.7% of the patients with scvere liver histology change, and should be treated with antivirus.2. Chronic HBV infection with PNALT still has the potential to progress in liver histology.3. Chronic HBV infection with PNALT should be given individualized treatment, liver histology change in those with family history, HBeAg negative, lower HBV DNA is more severe, so for CHB patients with PNALT, accompany with family history, HBeAg negative, lower HBV DNA in patients with chronic hepatitis B if not for a liver biopsy, also suggested for antiviral treatment.Background The progress of hepatitis B is a long process, as the extension of time, the infection of infected liver cells gradually increased. The currently accepted overall goal of therapy for chronic hepatitis B is:maximize the long-term restrain or eliminate HBV, reduce liver inflammation and fibrosis, slow down and stop disease progression, reduce and prevent the liver decompensation, cirrhosis and primary hepatocellular carcinoma (HCC). Now think that the immune clearance phase is the key to change the natural progression of hepatitis B stage, treatment is necessary in this stage, and due to the active participation of organism immune system, the possibility to achieve treatment goals is higher. The hepatitis B virus infection with PNALT usually in the early disease, and many research suggests the condition is relatively stable, so it was thought that antiviral treatment is unnecessary. But there were many study have shown that chronic HBV infection with PNALT, positive HBV DNA have varying degrees of liver damage, and there was the risk of disease progression, so some scholars suggested that antiviral therapy is necessary. According to the treatment of chronic hepatitis B prevention and control guidelines, CHB patients with elevated ALT should be treated, but how about the chronic HBV infections those with PNALT, whether antiviral treatment is necessary or not? For fear of increased risk of poor antiviral efficacy and drug resistance, most scholars suggest that chronic HBV infections with PNALT, positive HBV DNA should not be treated with antiviral.Objective To analyse the clinical curative effect of nucleos(t)ide antiviral therapy of chronic HBV infections with PNALT, positive HBV DNA. and compare the clinical effect with the moderately elevated ALT (1-2 x ULN) and significantly increased ALT(> 2 x ULN) of HBV infection in virological.Method According to the baseline ALT levels, all patients were divided into research group(CHB with PNALT) and control group 1 (ALT 1～2x ULN)and control group 2 (ALT> 2 x ULN), all patients accepted the nucleos(t)ide analogs antiviral treatment, and the antiviral clinical curative effect were compared in three groups. SPSS20.0 software package was used to statistical analysis, virological and serological response is obtained by using the life table method and clinical endpoint events (virological breakthrough) accumulation rate, incidence in progress.Results1. The general information of the patients:this study contain 256 cases, research group of 85 cases, control group 1 of 90 cases, control group 2 of 81 cases. Male 182 cases (71.1%), female 74 cases (28.9%), baseline ALT mean 79.88±61.15 U/L and HBV DNA mean 1.44±1.46 log 10, HBeAg positive 103 cases (40.2%), HBeAg negative 153 cases (59.8%), the average follow-up time of 3.13 years.2. The virological cumulative incidence of research group in 3 months,6 months and 9 months were 64%,96% and 100% respectively, the virological cumulative incidence of control group 1 in 3 months,6 months and 9 months were 63%, 91% and 99% respectively, and that of control group 2 in 3 months,6 months and 9 months were 73%,86%,95, three sets of annual average virological response rates were 71.43%,67.94% and 67.54% respectively.There was no statistical difference in the three groups (P>0.05).3. The HBeAg cumulative clearance rate of research group in 1 year,2 years,3 years were 15%,22%,22% respectively, that of control group 1were 34%,62% and 79% respectively, and that of control group 2 were 46%,64% and 64% respectively. The HBeAg annual average rate of three groups were 9.64%, 37.96% and 38.76% respectively. The HBeAg cumulative clearance rate of research group was lower than the two control group(P<0.05).4. The HBeAg cumulative conversion rate of research group in 1 year,2 years,3 years were 10%,22%,22%, that of control group 1 were 32%,54% and 67% respectively, and that of control group 2 were 44%,62% and 62% respectively. The HBeAg annual average rate in three groups were 9.2%,31.65% and 36.36% respectively. The HBeAg cumulative conversion rate of research group was lower than the two control group(P<0.05).5. The cumulative virological breakthrough rate of research group in 1 year,2 years,3 years were 4%,9% and 9% respectively, that of control group 1 were 2%,16% and 18% respectively, and that of control group 2 were 2%,5% and 7% respectively, The annual average incidence of virological breakthroughs in three groups were 3.68%,6.47% and 3.68% respectively, There was no statistical difference in the three groups (P=0.083).conclusion1. There was no statistical difference in virological response and virological breakthrough rate compared with control group, show that chronic HBV infections with PNALT, positive HBV DNA can also obtain clinical curative effect, did not increase the risk of drug resistance.2. The immunological response rate of research group is lower than that of the control group, it means that in the chronic hepatitis B patients with PNALT, the immune ability is relatively low, extend the antiviral treatment is required to gain a better immunological response. CHB patients with PNALT were advised to choose a high efficiency low resistance antiviral drugs.Background Hepatitis B virus (HBV) infection is a serious global public health problem. There are about 2 billion HBV infections worldwide, of which 3.5-4.0 million for chronic infections, about 60-100 million people die each year from liver failure caused by HBV infection, liver cirrhosis and HCC. Several studies showed the progression of chronic hepatitis B disease is associated with HBV loads. Therefore, inhibit HBV replication, can slow down disease progression, stable liver cells, reducing liver cirrhosis and HCC and HBV infection related death. Nucleos(t)ide analogues antiviral drug has become the most choice of CHB patients and clinicians. However, because Nucleos(t)ide analogues antiviral drug could not eliminate HBVcccDNA, it could not completely clear hepatitis B virus in a short term. And long-term use of nucleos(t)ide analogues may lead to relapse after drug withdrawal, caused the early treatment effect offset. So for chronic hepatitis B patients with PNALT, whether antiviral treatment will increase the risk of recurrence, whether the treatment can reduce the occurrence of liver cirrhosis, liver cancer, and whether the antiviral treatment can improve the clinical outcomes in patients with PNALT?Objective To explore the risk of recurrence and the clinical outcome of antiviral treatment for the persistent normal ALT in patients with chronic hepatitis B.Method According to the baseline ALT, all patients were divided into research group and control group 1, control group 2, and all the patients accepted nucleos(t)ide analogs antiviral treatment. To describ the incidence of recurrence after the drug was stopped, and the incidence of liver cirrhosis and liver cancer. SPSS20.0 software package was used to statistical analysis, relapse after drug withdrawal is obtained by using the life table method and clinical endpoint events (liver cirrhosis, liver cancer and death) accumulation rate, incidence in progress.Results1. This study selected 256 cases in total, research group of 85 cases, control group 190 cases, control group 2 of 81 cases,182 cases (71.1%) of men,74 cases (28.9%) of women, baseline ALT mean 79.88±61.15 U/L and HBV DNA mean 1.44±1.46 log10, HBeAg positive for 103 cases (40.2%), HBeAg negative 153 cases (59.8%), the average follow-up time of 3.13 years. Historical control group 256 cases, male 190 cases (74.2%), female 66 cases (25.8%), baseline ALT mean 77.32±20.68 U/L and HBV DNA mean 7.13±8.20 log10, HBeAg positive for 105 cases (41%), HBeAg negative 151 cases (59%), the average follow-up time of 3.63 years.2. In this study,66 patients with standard drug withdrawal,40 cases (59.5%) of recurrence after the drug was stopped. The cumulative recurrence rates in 6 months of research group and control group 1, control group 2 were 15%,37%, 16%. The cumulative recurrence rates in 12 months of research group and control group 1, control group 2 were 49%,61%,43%. And the cumulative recurrence rates in 18 months of research group and control group 1, control group 2 were 49%,66%,69%, and annual average incidence of three groups were 5.08%,9.75% and 9.3% respectively. There was no statistically significant difference in three groups (P> 0.05).3. The cumulative incidence of liver cirrhosis in 5 years of the research group, control group 1, control group 2 were 12%,12% and 9%, respectively, and the annual average incidence of liner cirrhosis were 1.97%,1.56% and 1.09% respectively. No statistically significant difference (P> 0.05).4. The cumulative incidence of liver cirrhosis of treatment group in 1 year,3 years,5 years,8 years were 1%,2%,13% and 17% respectively, and that of the historical control group in 1 year,3 years,5 years,8 years were 0,13%,24% and 13% respectively. In the two groups the annual average incidence of liver cirrhosis were 2.24%,5.6% respectively. Comparison between the two groups there was statistically significant difference (P< 0.05).5. The cumulative incidence of liver cancer of treatment group in 1 year,3 years, 5 years,8 years were 0%,1%,1%,1%, and that of the historical control group in 1 year,3 years,5 years,8 years were 0,9%,13% and 9% respectively. The annual average incidence of liver cancerin in the treatment group and historical control group were 0.4%and 0.4% respectively. Comparison between the two groups there was statistically significant difference (P< 0.05).conclusion(1) There was no statistical differences of recurrence after discontinuation between chronic hepatitis B patients with PNALT and those with elevated ALT, show that normal ALT in patients with chronic hepatitis B antiviral treatment did not increase the risk of recurrence after drug withdrawal.(2)After the antiviral treatment, there was no difference between the cumulative incidence of liver cirrhosis in the chronic hepatitis B with PNALT ang those with elevated ALT. Compared with the historical nature controls, the cumulative incidence of liver cirrhosis and liver cancer in the treatment group decreased obviously, shows antiviral therapy can improve the clinical outcomes of CHB patients with PNALT.
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