Chronic hepatitis B is an important public health issue in China. The drugs used as the antiviral therapy for hepatitis B are mainly interferons and nucleos( t) ide analogues. Although these drugs have realized persistent HBV inhibition in most patients,a large number of patients cannot achieve immune control and functional cure. It is believed that in the future,with the research and development of new target drugs,we will defeat HBV in the way we defeated HCV.

With the prevalence of obesity around the world,the incidence rate of hepatitis B virus( HBV) infection complicated by metabolic syndrome( MS) is increasing year by year,and such patients have become a special population in patients with chronic HBV infection. In recent years,the research on the features of this disease and diagnosis and treatment strategies has become a hot topic in the field of liver disease. MS not only increases the risk of liver fibrosis and cirrhosis in chronic hepatitis B( CHB) patients,but also reduces the response to antiviral therapy. Therefore,as for patients with HBV infection,especially CHB patients with suboptimal response to antiviral therapy,MS and its components should be considered. Screening and monitoring of liver cirrhosis should be performed for patients with HBV infection complicated by MS to guide the development of proper treatment regimens.

Chronic hepatitis B virus( HBV) infection is one of the major disease burdens worldwide. At present,the antiviral therapy for hepatitis B includes interferons and nucleos( t) ide analogues. Current therapeutic regimens based on these drugs cannot significantly increase the proportion of patients with functional cure. With a better understanding of HBV replication cycle and specific virus- host cell interactions,this article summarizes and reviews the advances in the research and development of new drugs for HBV with a focus on different action targets during the above processes.

Chronic hepatitis B is still one of the most important chronic diseases in China because of its high relevance to liver cirrhosis and hepatic cell cancer( HCC). Currently,interferon and nucleos( t) ide analogues are two main treatments for chronic hepatitis B,but they have advantages and disadvantages. More investigations are needed to explore better ways for treating this disease,and combination therapy might be one of the options. This article analyzes the advances in various combination therapies and points out views about the selection of combination therapies and patients.

Increasing attentions have been paid to the antiviral therapy for special populations with chronic hepatitis B( CHB),including patients co- infected with HIV,HDV,or HCV,children and adolescents,pregnant women,patients with chronic kidney diseases,and patients who require chemotherapy or immunosuppressive therapy. The indications for antiviral therapy,drug selection and adjustment,and treatment course in special populations with CHB have become the hot topics of clinical research. In recent years,all guidelines for the prevention and treatment of CHB have provided a summary of key considerations in the standardized management of these populations. However,the strength of recommendations for antiviral therapy in these populations is not high. In order to obtain a strong medical evidence for antiviral therapy in these populations,we should standardize clinical management processes and carry out high- quality cohort studies based on the previous research.

Liver fibrosis / cirrhosis is the outcome of the progression of chronic hepatitis B and is associated with liver events and long- term prognosis. Effective antiviral therapy can delay or even reverse disease progression. Therefore,assessment of liver fibrosis degree before and during treatment is of great importance in initiating antiviral therapy,developing therapeutic regimens,and monitoring antiviral effects and complications. The semi- quantitative histological scoring system is widely acknowledged in the assessment of liver fibrosis degree and is an important basis for the initiation of antiviral therapy for hepatitis B,as well as a method commonly used for efficacy surveillance. Morphological and structural quantitative methods provide objective histological assessment of liver fibrosis and may cover the shortage of conventional semi- quantitative scoring system. Non- invasive methods for the assessment of liver fibrosis may reduce but not completely substitute liver histological examinations; a consensus has not been reached on their cut- off values to make decisions to initiate antiviral therapy,but such non- invasive methods can provide rich information on therapeutic effect and long- term prognosis.

Primary biliary cholangitis is a chronic intrahepatic cholestatic liver disease and has increasing incidence and prevalence rates,as is reported in the literature. Examination of specific antibodies including serum anti- mitochondrial antibody subtype M2 and liver histopathological examination help to make a definite diagnosis of this disease. Ursodeoxycholic acid( UDCA) is often used for the treatment of this disease,but patients with an unsatisfactory biochemical response to UDCA tend to have rapid disease progression. At present,there are no effective treatment methods for such patients. The addition of budesonide,fenofibrate,bezafibrate,or obeticholic acid may be effective in these patients,but this needs to be verified by further clinical studies.

Objective To investigate the clinical effect of 24- week tenofovir disoproxil fumarate( TDF) sequential therapy in HBeAg- positive chronic hepatitis B( CHB) patients with suboptimal serological response to 48- week pegylated interferon- α- 2a( Peg- IFN- α- 2a) monotherapy. Methods A total of 21 patients who did not achieve HBeAg seroconversion after the 48- week Peg- IFN- α- 2a monotherapy at a dose of 180 μg / week were enrolled. Among these patients,11 were given TDF 300 mg / d in addition,the withdrawal of Peg- IFN- α- 2a after 12 weeks,and TDF monotherapy for 12 weeks; 10 were given sequential adefovir dipivoxil( ADV) monotherapy at a dose of 10 mg / d for 24 weeks. The indicators including HBV DNA,liver and renal function,and HBV serological markers were measured at weeks 12 and 24 of treatment,and the clinical outcome was compared between the two groups. The independent samples t- test was used for comparison of normally distributed continuous data between groups and the paired t- test was used for comparison of normally distributed continuous data within one group; the Mann- Whitney U test was used for comparison of non- normally distributed continuous data between groups. The Fisher's exact test was used for comparison of categorical data. Results At weeks 12 and 24 of treatment,there were no significant differences in HBs Ag and HBeAg levels between groups( both P > 0. 05). At week 24 of treatment,there was no significant difference in HBeAg seroconversion rate between the TDF group and the ADV group [18. 2%( 2 /11) vs 10. 0%( 1 /10),P > 0. 05]. At weeks 12 and 24 of treatment,the TDF group had significant reductions in HBeAg compared with baseline( 1. 75 ± 0. 59 log10 S / CO、1. 61 ± 0. 70 log10 S / CO vs1. 86 ± 0. 58 log10 S / CO,P = 0. 017 and 0. 027). At week 24 of treatment,the TDF group had a significantly lower alanine aminotransferase( ALT) level than the ADV group[21. 0( 15.0-27.0) U/L vs 33. 0( 21. 5-63. 5) U/L,P =0.046]. There were no significant differences in estimated glomerular filtration rate at weeks 12 and 24 of treatment between the two groups( both P > 0. 05). Conclusion As for CHB patients with suboptimal serological response to 48- week Peg- IFN- α- 2a monotherapy,addition of TDF for 12 weeks and then TDF monotherapy for 12 weeks helps to achieve greater reductions in serum ALT and HBeA g levels compared with sequential ADV therapy.

Objective To investigate the clinical effect of entecavir( ETV) combined with thymosin in the treatment of HBe Ag- positive chronic hepatitis B( CHB) patients. Methods A total of 108 HBe Ag- positive CHB patients who were treated in Department of Infectious Diseases in our hospital from March 2012 to March 2015 were enrolled,and according to the parallel,single- blind,randomized controlled principles,the patients were divided into control group( 54 patients) and observation group( 54 patients). The patients in both groups were given comprehensive medical treatment; the patients in the control group were treated with ETV alone,and those in the observation group were treated with ETV combined with thymosin. The changes in liver function parameters,virological parameters,immune indices,and liver fibrosis indicators were compared between the two group. The t- test was used for comparison of continuous data between groups,and the chi- square test was used for comparison of categorical data between groups. Results After 48 weeks of treatment,there were significant differences between the observation group and the control group in the liver function parameters albumin / globulin ratio( 1. 73 ± 0. 57 vs 1. 50 ± 0. 51,t =2. 210,P < 0. 05),alanine aminotransferase( 42. 58 ± 14. 32 U / L vs 54. 26 ± 18. 78 U / L,t = 3. 634,P < 0. 05),aspartate aminotransferase( 35. 79 ± 10. 33 U / L vs 49. 97 ± 17. 84 U / L,t = 5. 055,P < 0. 05),and total bilirubin( 18. 89 ± 6. 02 μmol / L vs 25. 24 ± 9. 06μmol /L,t = 4. 290,P < 0. 05). After 48 weeks of treatment,there were significant differences between the observation group and the control group in the liver fibrosis indicators laminin( 65. 34 ± 11. 02 ng / ml vs 102. 57 ± 16. 41 ng / ml,t = 13. 840,P < 0. 001),hyaluronic acid( 91. 68 ± 11. 53 ng / ml vs 151. 23 ± 16. 71 ng / ml,t = 21. 555,P < 0. 001),type IV collagen( 81. 02 ± 12. 64 μg / ml vs 118. 47 ±18. 01 μg / ml,t = 12. 507,P < 0. 001),and procollagen III( 70. 44 ± 13. 06 μg / ml vs 91. 57 ± 17. 16 μg / ml,t = 7. 200,P < 0. 001). At weeks 12,24,and 48 of treatment,the observation group had significantly higher HBe Ag clearance rates than the control group( 29. 63% /46. 30% /57. 41% vs 12. 96% /22. 22% /25. 93%,χ2= 4. 475,6. 948,and 11. 009,all P < 0. 05). After 48 weeks of treatment,compared with the control group,the observation group had a significantly lower serum level of interleukin- 4( 2. 69 ± 1. 23 pg / ml vs 4. 38 ±1. 44 pg / ml,t = 6. 558,P < 0. 001) and a significantly higher level of interferonγ( 1. 82 ± 0. 89 pg / ml vs 1. 12 ± 0. 56 pg / ml,t = 4. 812,P < 0. 001). There was no significant difference in the incidence rate of adverse events between the observation group and the control group( 3. 70% vs 1. 85%,χ2= 0. 343,P = 0. 558). Conclusion In HBeA g- positive CHB patients,ETV combined with thymosin can promote the recovery of liver function,regulate immune function,improve HBeA g clearance rate,and inhibit the process of liver fibrosis.

Objective To investigate the impact of treatment with nucleos( t) ide analogues on quality of life( Qo L) in patients with chronic hepatitis B( CHB),as well as proper nursing measures. Methods A total of 102 CHB patients who were treated in Department of Infectious Diseases,Nanfang Hospital,Southern Medical University from March 2010 to July 2014 were enrolled and divided into continuous treatment group( 54 patients) and drug withdrawal group( 48 patients). The 36- item short- form health survey( SF- 36) was used to measure Qo L. The patients in the treatment group were evaluated before treatment and at 96 weeks of treatment,and those in the drug withdrawal group were evaluated at the time of drug withdrawal and at 48 weeks after drug withdrawal. The t- test was used for comparison of continuous data between groups,and the chi- square test was used for comparison of categorical data between groups. The logistic regression analysis was performed for univariate and multivariate analyses. Results Compared with before treatment,the continuous treatment group had significant increases in the scores on the domains of physiological function,role physical,bodily pain,and general health after 96 weeks of antiviral therapy( physiological function: 94. 91 ± 7. 11 vs 92. 13 ± 10. 58,t =- 2. 924,P < 0. 05; role physical: 81. 94 ± 24. 96 vs71. 76 ± 34. 01,t =- 2. 623,P < 0. 05; bodily pain: 87. 72 ± 8. 64 vs 82. 85 ± 12. 88,t =- 3. 576,P < 0. 05; general health: 59. 63 ±14. 59 vs 53. 52 ± 16. 79,t =- 3. 786,P < 0. 05). As for psychological quality,the continuous treatment group had a significant increase in the subscale of mental health( 67. 30 ± 18. 94 vs 75. 56 ± 15. 53,t =- 3. 883,P < 0. 001),while there were no significant improvements in other subscales. At 48 weeks after drug withdrawal,the drug withdrawal group had significant increases in role physical( 84. 20 ± 18. 97 vs72. 49 ± 24. 38,t =- 2. 768,P < 0. 05),general health( 69. 28 ± 22. 94 vs 56. 41 ± 18. 27,t =- 3. 206,P < 0. 05),and mental health( 75. 02 ± 16. 03 vs68. 94 ± 14. 07,t =- 2. 078,P < 0. 05). The multivariate analysis showed that marital status was associated with the improvement in QoL after antiviral therapy( odds ratio = 11. 61,95% CI: 2. 28- 59. 00,P = 0. 003); the unmarried patients had better improvements in Qo L compared with the married ones,especially physiological function( t =- 2. 176,P = 0. 034),role physical( t =- 2. 173,P = 0. 034),and role emotional( t =- 2. 811,P = 0. 007). Conclusion Antiviral therapy can improve the Qo L and mental health of CHB patients. Effective psychological intervention is necessary for CHB patients,especially married CHB patients.

Objective To investigate the clinical effect of entecavir in the treatment of patients with chronic hepatitis B( CHB) complicated by tuberculosis during anti- tuberculosis treatment. Methods A retrospective study was performed for the clinical data of 95 patients with CHB complicated by tuberculosis,and according to the application of entecavir antiviral therapy during anti- tuberculosis treatment,these patients were divided into treatment group and control group. The changes in clinical biochemical parameters and prognosis after treatment were compared between the two groups. The t- test or Mann- Whitney U test were used for comparison of continuous data between groups,and the chi- square test was used for comparison of categorical data between groups. Results During the treatment,compared with the treatment group,the control group had significantly higher alanine aminotransferase [382. 7( 260. 7- 635. 9) U / L vs 143. 3( 97. 9-260. 4) U / L,Z =- 4. 225,P < 0. 001] and aspartate aminotransferase [280. 7( 197. 6- 461. 8) U / L vs 93. 8( 67. 3- 156. 9) U / L,Z =- 4. 637,P < 0. 001]and significant increases in total bilirubin [157. 4( 139. 7- 269. 6) μmol / L vs 106. 8( 88. 3- 187. 1) μmol / L,Z =- 2. 671,P = 0. 008] and the proportion of patients with jaundice( 63. 2% vs 34. 2%,χ2= 7. 650,P = 0. 007). Compared with the treatment group,the control group had a significantly prolonged prothrombin time( 22. 5 ± 15. 5 s vs 17. 3 ± 9. 7 s,t = 2. 553,P = 0. 012)and a significantly lower platelet count [( 131. 0 ± 69. 4) × 109/ L vs( 181. 7 ± 105. 6) × 109/ L,t = 2. 826,P = 0. 004] during treatment.Compared with the treatment group,the control group had significant increases in the proportions of patients with liver failure( 42. 1% vs15. 8%,χ2= 7. 306,P < 0. 001) and patients who were forced to stop all or part of antitubercular agents due to liver impairment during treatment( withdrawal of all antitubercular agents: 17. 5% vs 2. 6%,χ2= 4. 952,P = 0. 026; withdrawal of part of antitubercular agents: 68. 4%vs 15. 8%,χ2= 25. 330,P < 0. 001). Conclusion During the anti- tuberculosis treatment for patients with CHB complicated by tuberculosis,entecavir antiviral therapy can effectively reduce the incidence of liver injury during anti- tuberculosis treatment and ensure the effect and safety of anti- tuberculosis treatment; therefore,it holds promise for further clinical research.

Objective To investigate the clinical effect of entecavir combined with antituberculosis therapy in patients with tuberculosis complicated by chronic HBV infection. Methods A total of 108 patients with tuberculosis complicated by chronic HBV infection were divided into entecavir group with 58 patients and control group with 50 patients. The patients in the entecavir group were given entecavir from1 month before antituberculosis therapy to the end of antituberculosis therapy,and those in the control group were given antitubercular agent alone. The incidence of liver injury and clinical symptoms,time to appearance of abnormal liver function,and time to liver function recovery were compared between the two groups. The two- independent- samples t test was used for comparison of continuous data between groups,and the chi- square test was used for comparison of categorical data between groups. Results Compared with the control group,the entecavir group had significantly higher incidence rates of abnormal liver function( 29. 31% vs 64. 00%,χ2= 8. 475,P < 0. 05) and clinical symptoms of liver injury( 17. 24% vs 28. 00%,χ2= 5. 534,P < 0. 05). There were significant differences in the time to appearance of abnormal liver function( 25. 1 ± 10. 2 d vs 20. 1 ± 8. 9 d,t = 2. 675,P < 0. 05) and time to liver function recovery( 26. 5 ± 9. 8 d vs 32. 6 ±11. 2 d,t = 3. 778,P < 0. 05). Conclusion Entecavir can significantly reduce the incidence of liver injury caused by antituberculosis therapy,postpone the time to appearance of liver injury,and accelerate liver function recovery in patients with tuberculosis complicated by chronic HBV infection.

Objective To investigate the clinical effect of alprostadil combined with entecavir in the treatment of HBV- related liver failure complicated by ascites. Methods A total of 84 patients with HBV- related liver failure complicated by ascites who were hospitalized and treated in No. 97 Hospital of PLA from September 2011 to June 2014 were enrolled and randomly divided into treatment group( 42 patients)and control group( 42 patients). The patients in both groups were given conventional treatment for liver protection,jaundice clearance,diuresis,and albumin nutritional support. The patients in the control group were given entecavir in addition,while those in the treatment group were given alprostadil combined with entecavir in addition. The liver function parameters [total bilirubin( TBil),alanine aminotransferase( ALT),and aspartate aminotransferase( AST) ],prothrombin activity( PTA),HBV DNA load,clinical outcome,24- hour urine volume,and ascites regression before and after treatment were observed and recorded. The t- test was used for comparison of continuous data between groups,and the chi- square test was used for comparison of categorical data between groups. Results Both groups had significant changes in the liver function parameters( TBil,ALT,and AST),PTA,and HBV DNA load after treatment( all P < 0. 05). There were significant differences in TBil,ALT,AST,and PTA after treatment between the treatment group and the control group( TBil: 197. 4 ± 47. 6 μmol / L vs287. 5 ± 150. 6 μmol / L,t = 2. 30,P < 0. 05; ALT: 189. 4 ± 63. 8 U / L vs 263. 4 ± 79. 5 U / L,t = 2. 73,P < 0. 05; AST: 138. 7 ± 87. 5 U / L vs 250. 8 ± 90. 4 U / L,t = 3. 43,P < 0. 05; PTA: 63. 5% ± 17. 0% vs 45. 5% ± 15. 1%,t = 2. 60,P < 0. 05). The treatment group had significantly higher marked response rate and overall response rate concerning clinical outcome than the control group( marked response rate:40. 48% vs 28. 57%,χ2= 4. 32,P < 0. 05; overall response rate: 85. 71% vs 66. 67%,χ2= 4. 20,P < 0. 05). The treatment group also had significantly higher marked response rate and overall response rate concerning ascites regression than the control group( marked response rate: 47. 62% vs 23. 81%,χ2= 13. 20,P < 0. 05; overall response rate: 88. 10% vs 52. 38%,χ2= 12. 81,P < 0. 05). Conclusion In patients with severe hepatitis B complicated by ascites,alprostadil combined with entecavir has good clinical effect and safety and can effectively improve the prognosis. Therefore,it holds promise for clinical application.

Objective To investigate the clinical value of indocyanine green retention rate at 15 min( ICG R15) in the condition analysis and prognostic evaluation of patients with acute- on- chronic liver failure( ACLF),and to provide a reference index for condition analysis and prognostic evaluation of patients with ACLF. Methods A total of 127 ACLF patients who were admitted to our hospital from August2013 to January 2016 were enrolled,and according to the clinical stage,they were divided into early- stage group,medium- stage group,and late- stage group. The ICG R15,Model for End- Stage Liver Disease( MELD) score,and prothrombin time( PT) were compared between the patients with different clinical stages. According to the prognosis at 90 days,the patients were divided into survival group and death group,and the above indicators were compared between the two groups. The clinical value of ICG R15 in condition analysis and prognostic evaluation was summarized. The independent samples t- test or a one- way analysis of variance was used for continuous data,the least significant difference method was used for comparison between any two groups,and the chi- square test was used for categorical data.Results Compared with the early- stage group,the medium- stage group and late- stage group had significantly higher ICG R15( 53. 96% ±10. 01% /54. 23% ± 9. 21% vs 44. 00% ± 9. 21%,P < 0. 05),PT( 26. 87 ± 6. 84 s /28. 43 ± 3. 61 s vs 19. 79 ± 2. 82 s,P < 0. 05),and MELD score( 31. 56 ± 4. 17 /32. 87 ± 3. 28 vs 24. 00 ± 3. 85,P < 0. 05). The death group had significantly higher ICG R15,PT,and MELD score than the survival group( ICG R15: 53. 91% ± 5. 83% vs 45. 03% ± 4. 33%,t = 9. 85,P < 0. 05; PT: 29. 85 ± 3. 52 s vs 21. 35 ± 3.18 s,t = 14. 20,P < 0. 05; MELD score: 33. 81 ± 4. 67 vs 25. 30 ± 4. 02,t = 10. 99,P < 0. 05). With an ICG R15 of 52%,a PT of 29 s,and a MELD score of 32 as cut- off values,there were significant differences in mortality rate between the patients with different levels of indicators( ICG R15: 22. 39% vs 64. 29%,χ2= 8. 831,P < 0. 05; PT: 25. 71% vs 61. 40%,χ2= 6. 263,P < 0. 05; MELD score: 21. 54% vs 62. 90%,χ2= 7. 583,P < 0. 05). Conclusion With the aggravation of the condition of ACLF and the reduction in prognosis,PT and MELD score increase gradually,and ICG R15 also increases. We can comprehensively evaluate patients' condition and clinical prognosis in an early stage based on the changes in the above indicators.

Objective To investigate the clinical guiding significance of Guideline for diagnosis and treatment of herb- induced liver injury in the diagnosis of herb- induced liver injury( HILI). Methods A retrospective analysis was performed for the clinical data of 595 hospitalized patients who were admitted to 302 Hospital of PLA from January 2009 to January 2014 and diagnosed with HILI according to HILI diagnostic strategies recommended by American College of Gastroenterology. The chi- square test was used for comparison of categorical data between groups. Results According to the Guideline for diagnosis and treatment of HILI,all 595 patients( 100%) were diagnosed with suspected HILI,234( 39. 3%) were diagnosed with clinical HILI,and 52( 8. 7%) were diagnosed with definite HILI. Among the patients with clinical and definite HILI,85. 0% and 94. 2%,respectively,had a clinical type of cell injury,and 52. 6% and 42. 3%,respectively,had a severe disease. There were no significant differences in prognosis between the patients with suspected,clinical,and definite HILI,and81. 5%,82. 5%,and 80. 8%,respectively,were cured. Conclusion Guideline for diagnosis and treatment of HILI can effectively guide the diagnosis of HILI,avoid misdiagnosis in clinical practice,and guarantee the safe application of Chinese herbal medicine. Its clinical guiding significance in the diagnosis of HILI awaits more prospective studies.

Objective To investigate the antioxidant effect of matrine and its clinical effect in the treatment of rats with nonalcoholic steatohepatitis( NASH). Methods A total of 30 rats were randomly divided into three groups: control group,NASH group,and matrine group,with 10 in each. A high- fat diet was used to establish the rat model of NASH,and matrine was given by gavage for treatment at a dose of36 mg·kg- 1·d- 1. The changes in body weight and liver weight were observed in all rats. HE staining was used to observe the histopathological changes of the liver. The serum levels of alanine aminotransferase( ALT) and aspartate aminotransferase( AST) and the content of reduced glutathione( GSH),superoxide dismutase( SOD),and malondialdehyde( MDA) in liver tissue were measured. A one- way analysis of variance was used for the comparison between multiple groups,and the SNK- q test was used for further comparison between any two groups. Results Compared with the NASH group,the matrine group had significant reductions in the serum levels of ALT and AST( ALT:52. 0 ± 3. 0 U / L vs 41. 8 ± 3. 7 U / L,P < 0. 001; AST: 233. 6 ± 9. 4 U / L vs 170. 1 ± 1. 8 U / L,P < 0. 001). The matrine group showed marked improvement in the histopathological changes of the liver compared with the NASH group. Compared with the NASH group,the matrine group had significantly increased content of SOD and GSH in liver tissue( SOD: 17. 7 ± 2. 0 μg / mg vs 27. 0 ± 3. 6 μg / mg,P < 0. 001;GSH: 16. 5 ± 1. 6 U / mg vs 28. 5 ± 2. 1 U / mg,P < 0. 001) and significantly reduced content of MDA( 22. 9 ± 1. 9 nmol / mg vs 17. 8 ± 1. 8nmol / mg,P < 0. 001). Conclusion Matrine has an antioxidant effect and a marked clinical effect in the treatment of rats with NASH.