Changes in serum levels of hepatitis B virus markers after interferon treatment

The effect of interferon (IFN) treatment on serum levels of pre-S antigens [pre-S(1) antigen, pre-S(2) antigen, polymerized human serum albumin receptor (pAR)] which are coded by the pre-S region of hepatitis B virus DNA (HBV-DNA), and HBV-markers was analyzed in 23 patients with chronic hepatitis B. One year after IFN treatment, 4 patients (Group C) became HBeAg negative. Six patients (Group B) transiently became HBeAg-negative, but reverted to HBeAg positive. Thirteen patients (Group A) remained HBeAg positive. All of the patients remained HBsAg-positive. Initiation of IFN treatment was rapidly followed by reduction or loss of DNA-P in the serum whether the patients became HBeAg negative or remained positive, and whether serum transaminase (S-GPT) levels became normal or not after IFN treatment. Group C patients, in whom pre-S antigens decreased rapidly during IFN treatment and disappeared before S-GPT levels normalized, became HBeAg negative one year after IFN treatment. Anti-pAR was detected in three out of these 4 patients. In contrast, Group A and Group B patients, in whom pre-S antigens decreased slowly during IFN treatment and did not disappear in spite of those patients being transiently negative for HBeAg and DNA-P, remained HBeAg positive with elevated S-GPT levels one year after IFN treatment. Anti-pAR was almost undetectable. These results suggest that testing for pre-S antigens is more useful for determining the prognosis of patients with chronic hepatitis B treated with IFN than testing for HBsAg, HBeAg and DNA-P.     

Changes of pre-Sl and pre-S2 antigens in sera of patients with hepatitis B virus infection

Polypeptides encoded by the pre-Sl and pre-S2 genes of hepatitis B virus (HBV) (pre-Sl antigen and pre-S2 antigen) were detected by enzyme-linked immunosorbent assay (ELISA) in 137 serum samples of patients with HBV infection. The HBV-DNA level closely correlated with the titer of pre-S antigens. However, HBV-DNA levels more closely correlated with the titer of the pre-Sl antigen [HBV-asymptomatic carrier (ASC): n=40, r=0.800, P<0.01; chronic hepatitis B (CH): n=60, r=0.730, P<0.01] than with the titer of the pre-S2 antigen [ASC: r=0.675, P<0.01; CH: r=0.575,P<0.01]. Thirty patients with CH, in whom hepatitis e antigen (HBeAg) was cleared after acute exacerbation (AE) [alanine aminotransferase (ALT) level> 200 IU/L] and the ALT level normalized, were followed for 12 months and classified into two groups: Group 1, those in whom HBeAg reappeared with an elevated ALT level within 12 months, and Group 2, those in whom HBeAg was persistently cleared from the serum and a normal ALT level continued. Of the 30 patients, 24 (80%) were classifed into Group 1 and 6 (20%) were classified into Group 2. Changes in serum levels of HBV markers a month before and after AE were observed. The HBV-DNA level and DNA-P activity became negative after AE in both groups. The titer of pre-Sl antigen also decreased after AE, and no significant differences were observed between Group 1 and Group 2. In contrast, the titer of pre-82 antigen and pAR activity decreased more significantly in Group 2 than in Group 1. These results suggest that the detection of the pre-S2 antigen and pAR activity in sera seems to be more useful as a prognostic test for patients with HBV infection than the detection of pre-Sl antigen, HBV-DNA, DNA-P or HBeAg.     

The effect of recombinant alpha-interferon treatment on serum levels of hepatitis B virus-encoded proteins in man

The effect of alpha-interferon treatment on serum levels of hepatitis B virus-encoded proteins was analyzed in eight patients with chronic type B hepatitis who participated in a pilot study of interferon therapy. Three individuals became HBsAg-negative, 4 lost HBeAg but remained HBsAg-positive and 1 remained positive for both HBsAg and HBeAg. Initiation of interferon treatment was rapidly followed by reduction or loss of hepatitis B virus DNA in the serum but by little immediate change in hepatitis B virus antigen levels. Changes in hepatitis B virus antigens were usually delayed. Loss of HBsAg from the serum was preceded by the sequential disappearance of pre-S-encoded proteins (pre-S1 and polymerized human serum albumin) and HBeAg. In patients who lost HBeAg but remained HBsAg-positive, serum levels of pre-S1 and polymerized human serum albumin usually, but did not always, decrease. The individual who remained HBsAg- and HBeAg-positive had unchanged serum levels of pre-S1, polymerized human serum albumin and HBsAg. These results suggest that alpha-interferon inhibits hepatitis B virus DNA replication but has little direct effect on synthesis of hepatitis B virus gene products.     

Changes of pre-S1 and pre-S2 antigens in sera of patients with hepatitis B virus infection

Polypeptides encoded by the pre-S1 and pre-S2 genes of hepatitis B virus (HBV) (pre-S1 antigen and pre-S2 antigen) were detected by enzyme-linked immunosorbent assay (ELISA) in 137 serum samples of patients with HBV infection. The HBV-DNA level closely correlated with the titer of pre-S antigens. However, HBV-DNA levels more closely correlated with the titer of the pre-S1 antigen [HBV-asymptomatic carrier (ASC): n = 40, r = 0.800, P less than 0.01; chronic hepatitis B (CH): n = 60, r = 0.730, P less than 0.01] than with the titer of the pre-S2 antigen [ASC: r = 0.675, P less than 0.01; CH: r = 0.575, P less than 0.01]. Thirty patients with CH, in whom hepatitis e antigen (HBeAg) was cleared after acute exacerbation (AE) [alanine aminotransferase (ALT) level greater than 200 IU/L] and the ALT level normalized, were followed for 12 months and classified into two groups: Group 1, those in whom HBeAg reappeared with an elevated ALT level within 12 months, and Group 2, those in whom HBeAg was persistently cleared from the serum and a normal ALT level continued. Of the 30 patients, 24 (80%) were classified into Group 1 and 6 (20%) were classified into Group 2. Changes in serum levels of HBV markers a month before and after AE were observed. The HBV-DNA level and DNA-P activity became negative after AE in both groups. The titer of pre-S1 antigen also decreased after AE, and no significant differences were observed between Group 1 and Group 2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nucleoside analog‐interferon sequential therapy on patients with acute exacerbation of chronic hepatitis B

Aim: Nucleoside analog (NA)‐interferon (IFN) sequential therapy may enable the long‐term control of chronic hepatitis B (CHB) and the withdrawal of the nucleoside analog. We evaluated the efficacy of NA‐IFN sequential therapy for acute exacerbation of CHB. Methods: A total of 12 patients with acute exacerbation of CHB, nine of whom were positive for hepatitis B e antigen (HBeAg), were enrolled in this study. All the patients were treated with lamivudine 100 mg/day alone for 20 weeks, then with both IFN‐α 6 megaunits three times per week and lamivudine for 4 weeks, and lastly, with IFN‐α alone for 20 weeks. Patients whose serum alanine aminotransferase (ALT) level was normalized, whose serum hepatitis B virus (HBV) DNA level decreased to less than 5 log copies/mL, and HBeAg level was absent 24 weeks after the end of treatment were defined as having sustained virological response (SVR). The other patients were defined as having no response (NR). Results: Four out of nine (44.4%) HBeAg‐positive and all three HBeAg‐negative patients achieved SVR. The levels of serum alanine aminotransferase (ALT), HBV DNA and HBV core‐related antigen were similar between SVR and NR patients at baseline. Three of four patients (75.0%) whose serum HBeAg became negative at the end of treatment achieved SVR, while one of five (20.0%) whose serum HBeAg remained positive achieved SVR. Conclusion: NA‐IFN sequential therapy for patients with acute exacerbation of CHB enables the withdrawal of treatment and is particularly effective for patients whose serum HBeAg has become undetectable by the end of the IFN treatment.     

A randomised double-blind placebo-controlled trial of prednisolone therapy in HBeAg and HBV DNA positive Chinese patients with chronic active hepatitis B

Forty-one hepatitis B e antigen (HBeAg) and hepatitis B virus (HBV) DNA positive Chinese patients with chronic active hepatitis B were randomized to receive either prednisolone or placebo oral for 8 weeks. The prednisolone group received 60 mg daily for 2 weeks, 40 mg for 2 weeks, 20 mg for 2 weeks, 10 mg for 1 week and 5 mg for 1 week. In 18 patients receiving prednisolone, serum HBV DNA levels rose during the course of therapy, but dropped abruptly within 1 month of cessation of treatment. Conversely, their serum alanine aminotransferase (ALT) levels decreased during high doses of prednisolone therapy, and then became transiently elevated during the period of withdrawal of prednisolone. At 1 year from initial treatment, the serum HBV DNA and ALT levels were similar between the groups of patients treated with prednisolone or placebo. In the prednisolone treated group, 66.7% of patients became HBV DNA negative, 50% became HBeAg negative, and 33.3% seroconverted to antibody to HBeAg (anti-HBe). In the placebo treated group, 60.9% of patients became HBV DNA negative, 60.9% became HBeAg negative, and 56.5% seroconverted to anti-HBe. Hepatic decompensation was not noted in any of the prednisolone-treated patients. Thus, the effects of the withdrawal prednisolone therapy on serum ALT and HBV DNA levels was temporary, and no differences in serum viral markers or biochemical parameters of liver inflammation between these two groups were noted at the 1 year follow-up period.     

Immunohistochemical study of pre-S(2) antigen in liver and serum of patients with chronic hepatitis B

To evaluate the significance of pre-S(2) in the liver, the authors studied the relationship between serum and intrahepatic pre-S(2) in 27 patients with chronic hepatitis B. Intrahepatic expression of preS(2) was observed under light and electron microscopy and compared with that of HBsAg and HBcAg. All patients were positive for hepatic pre-S(2), and 25 for serum pre-S(2). Intrahepatic pre-S(2) expression was membranous or both membranous and cytoplasmic in 18 cases and was cytoplasmic in 9. The serum levels of pre-S(2) were significantly higher in cases whose intrahepatic pre-S(2) was membranous than in the cytoplasmic cases. These findings indicate that membranous expression of pre-S(2) reflects its secretion into the circulation. Intrahepatic pre-S(2) expression was found almost completely to resemble that of HBsAg on both light and electron microscopy. Membranous pre-S(2) was seen in the liver of 16 of 25 cases who were positive for intrahepatic HBcAg. In detailed studies of membranous pre-S(2) and HBcAg, both membranous pre-S(2) and HBcAg appeared in the liver of all 7 cases before or at the peak of acute exacerbation, but after it, membranous pre-S(2) was not found in 4 of 8 cases. These results suggest that disappearance of membranous pre-S(2) and HBsAg may be related to hepatic cell necrosis in some cases with acute exacerbation.     

核苷(酸)类似物序贯干扰素治疗乙型肝炎病毒e抗原阳性慢性乙型肝炎患者的临床观察

目的 观察HBeAg阳性慢性乙型肝炎(CHB)患者在核苷(酸)类似物抗病毒治疗基础上序贯聚乙二醇干扰素α-2a(PEG IFNα-2a)治疗48周血清HBsAg的变化.方法 6例HBeAg阳性CHB患者中,3例采用核苷(酸)类似物序贯PEG IFNα-2a治疗48周,3例维持原核苷(酸)类似物治疗方案,每12周采用实时PCR定量检测HBV DNA,采用时间分辨免疫荧光分析法检测HBsAg、抗-HBs、HBeAg、抗-HBe及抗-HBc.结果 核苷(酸)类似物序贯PEG lFNα-2a治疗48周后,3例序贯治疗患者血清HBsAg均消失,而维持原核苷(酸)类似物治疗患者血清HBsAg效价为100～320 IU/mL.结论 对核苷(酸)类似物治疗产生较好应答反应且伴有血清HBsAg效价明显下降的HBeAg阳性CHB患者,在核苷(酸)类似物抗病毒治疗基础上序贯PEG IFNα-2a治疗48周能有效促进血清HBsAg下降,并出现血清HBsAg消失的现象.     

Quantitative assessment of serum hepatitis B e antigen, IgM hepatitis B core antibody and HBV DNA in monitoring the response to treatment in patients with chronic hepatitis B

Virological response to treatment of chronic hepatitis B is defined as the loss of serum hepatitis B virus DNA (HBV DNA) and hepatitis B e antigen (HBeAg). The quantitative measurement of HBV DNA is useful for monitoring and predicting the response to therapy with interferon-α (IFN-α). In this study, we evaluated whether quantitative measurement of serum HBeAg and IgM antibody to hepatitis B core antigen (HBcAb) could also be used in this manner. Using a microparticle-capture enzyme immunoassay (IMx), a standard curve of fluorescence rate vs HBeAg concentration was constructed to provide quantitative results. The IgM HBcAb index was also measured using a microparticle enzyme immunoassay and serum HBV DNA was measured by a solution hybridization assay. We studied 48 patients who were initially positive for HBeAg and HBV DNA and who were treated with IFN-α2b. Their sera were serially evaluated for HBeAg concentration, and results were compared with HBV DNA levels. In the 14 patients who responded to IFN, similar disappearance curves were observed with good intraindividual correlation between the levels of the two markers. In the 34 non-responders, HBeAg levels decreased during treatment but never became negative; HBV DNA levels also decreased during treatment and became transiently undetectable in six patients, falsely suggesting treatment success. The IgM HBcAb index paralleled changes in alanine aminotransferase (ALT) concentration and did not provide additional information. Multiple logistic regression indicated that baseline ALT and HBeAg concentrations were independent predictors of the response to treatment and the addition of neither HBV DNA nor IgM HBcAb improved the model. We conclude that quantitative measurement of HBeAg provides information similar to that of HBV DNA in monitoring and predicting the response to treatment; this technique could be readily adaptable to clinical laboratories.     

Assay of hepatitis B virus DNA by polymerase chain reaction and its relationship to pre-S- and S-encoded viral surface antigens

The polymerase chain reaction was evaluated as a diagnostic tool in 72 chronic hepatitis B virus carriers. Hepatitis B virus DNA was detectable in the serum of HBsAg-positive virus carriers using aliquots as small as 100 al. The detection limit for cloned hepatitis B virus DNA was 100 ag. Primer pairs for different regions of the HBV genome resulted in different sensitivity. Detection of the amplified hepatitis B virus DNA by Southern blotting and subsequent scintillation counting or densitometry allowed a semiquantitative assay. Using several primer pairs in parallel for optimal detection, all HBeAg-positive HBsAg carriers, 80% of HBe antibody-positive symptomatic HBsAg carriers and 57% of asymptomatic HBe antibody-positive HBsAg carriers were found to have hepatitis B virus DNA in the serum. During antiviral therapy hepatitis B virus DNA disappeared by the polymerase chain reaction assay in patients who became HBeAg negative, but polymerase chain reaction detected a relapse earlier than did the conventional dot blot. Pre-S antigens were assayed in serum and liver samples from most chronic carriers by enzyme-linked immunosorbent assay and/or immunoblot. Although most viremic carriers were strongly positive for pre-S1 and pre-S2 antigens, some hepatitis B virus DNA-positive HBsAg carriers did not have detectable pre-S antigens, and vice versa. Our data show that assay of hepatitis B virus DNA in the serum by polymerase chain reaction is by far more proficient than by dot blot and that it cannot be replaced by serological assays of HBeAg or pre-S antigen.     

乙型肝炎病毒表面抗原阳性患者前-S1抗原和前-S2抗原与HBV DNA和HBV-M相关性分析

目的检测乙型肝炎病毒患者乙型肝炎病毒前-S1抗原（HBV pre-S1-Ag）、前-S2抗原（HBV pre-S2-Ag）、乙型肝炎病毒DNA（HBV DNA）和乙型肝炎病毒E抗原（HBeAg）,探讨其相关性和临床应用价值。方法应用酶联免疫测定法（ELISA）分别检测HBV pre-S1-Ag、HBV pre-S2-Ag和乙型肝炎病毒标志物（HBV-M）,荧光定量聚合酶链反应法（FQ-PCR）检测HBV DNA,并对检测结果进行统计学分析。结果 HBsAg阳性者中,pre-S1-Ag、pre-S2-Ag、HBV DNA阳性者分别为594例、541例、629例,其阳性率分别为66.29%、60.38%、70.20%。HBeAg阳性组pre-S1-Ag、pre-S2-Ag、HBV DNA的阳性率分别为90.21%、74.46%、93.32%,显著高于HBeAg阴性组的45.28%、48.01%、49.89%,差异有统计学意义（P〈0.01）。随着HBV DNA载量的增高,pre-S1-Ag、pre-S2-Ag、HBeAg阳性率随之增高。结论 pre-S1-Ag、pre-S2-Ag与HBV DNA和HBeAg阳性检出率具有显著相关性。联合检测pre-S1-Ag、pre-S2-Ag、HBV DNA及HBV-M,有助于HBV早期诊断、疗效观察和预后判断。     

Quantitative analysis of pre-S1 and pre-S2 in relation to HBsAg expression

Sera from four patients with acute hepatitis B and 87 patients with chronic hepatitis B were examined quantitatively for pre-S1 and pre-S2 antigens by solid-phase enzyme immunoassays. Pre-S1 and pre-S2 antigens were detected in HBsAg-positive sera irrespective of the presence of viral replicative markers, and their titers correlated with those of HBsAg (r = 0.74, p less than 0.01; r = 0.74, p less than 0.01, respectively). Sera positive for HBeAg showed higher titers of pre-S1 (p less than 0.01) and pre-S2 (p less than 0.01) antigens than sera negative for HBeAg. The titers of pre-S1 and pre-S2 antigens also correlated with the levels of HBV-associated DNA polymerase activity (r = 0.51, p less than 0.01; r = 0.59, p less than 0.01, respectively) and HBV-DNA (r = 0.50, p less than 0.01; r = 0.46, p less than 0.01, respectively). However, the ratios between the titers of pre-S antigens and HBsAg had no significant relationships with those viral replicative markers. These findings suggest that the expression of pre-S antigens is intimately related to the expression of HBsAg and that they are not useful as markers of viral replication. The ratios between the titers of pre-S antigens and HBsAg tended to be high in patients with chronic active hepatitis and high aminotransferase levels. This finding may have been due to the hepatic release of pre-S antigens, over-production of which may have some relationship to liver injury.     

Anti-pre-S responses and viral clearance in chronic hepatitis B virus infection.

Serial sera were collected prospectively during the clinical course of 13 HBsAg carriers with chronic liver disease and analyzed for ALT levels, pre-S1 and pre-S2 antigens and corresponding antibodies and other serological hepatitis B virus markers. In five patients, anti-pre-S1 and anti-pre-S2 antibodies became detectable in multiple serum samples, whereas in eight patients anti-pre-S was never detected or only appeared transiently during the follow-up. The first pattern was associated with normalization of ALT levels and undetectable pre-S antigens and viral DNA by the polymerase chain reaction assay at final follow-up. HBsAg clearance occurred in two of the five patients. The second pattern was one of persistence of HBsAg and pre-S antigens, associated with the presence of serum HBV DNA detectable by spot hybridization or polymerase chain reaction regardless of clinical outcome. These findings demonstrate the occurrence of anti-pre-S antibodies in chronic hepatitis B virus-induced liver disease and associate anti-pre-S appearance with the clearance of hepatitis B virus from serum.     

Histological improvement of chronic hepatitis B, and non-A, non-B with interferon treatment: application of a numerical scoring system for evaluating sequential morphologic changes

In order to assess the sequential changes of liver pathology after interferon therapy, 70 liver biopsy specimens, collected from 23 HBeAg-positive patients with chronic hepatitis B and 12 patients with chronic non-A, non-B hepatitis, were studied using a numerical scoring system proposed by Knodell et al. The biopsy specimens were obtained immediately prior to the administration of interferon and within one week following the termination of interferon therapy. Three patients with chronic hepatitis B were negative for DNA-polymerase (DNA-P) prior to the interferon administration. Ten patients (50%) lost DNA-P activity. HBeAg became negative in 8 patients (34.8%), of whom 2 seroconverted to anti-HBe. Serum alanine aminotransferase levels normalized in 9 patients with chronic hepatitis B, and non-A, non-B hepatitis. The total Histological Activity Index (HAI) scores in both patients with chronic hepatitis B, and non-A, non-B decreased significantly (P less than 0.001 and P less than 0.005, respectively) after interferon treatment. There was also a significant improvement (0.02 less than P less than 0.001) in each histological category except for fibrosis. When the changes of the HAI scores in patients with chronic hepatitis B were correlated to the outcome in the DNA-P and HBeAg/anti-HBe system after treatment, the histological improvement did not significantly correlate to the outcome of these serological parameters.     

Clinical, virologic and histologic outcome following seroconversion from HBeAg to anti-HBe in chronic hepatitis type B

Seventy consecutive HBsAg- and HBeAg-positive patients with biopsy-proven chronic hepatitis were followed prospectively with serial determinations of SGPT levels and hepatitis B virus serum markers including HBsAg, HBeAg, anti-HBe and hepatitis B virus DNA. During a period of 1 to 11 years (mean +/- S.D.: 5.0 +/- 2.3 years), 28 patients remained persistently HBeAg positive, most with continuing biochemical and histologic activity, while 41 cases seroconverted to anti-HBe. One patient became HBeAg and anti-HBe negative. After seroconversion, 87.8% of the cases showed sustained normalization of SGPT, and clearance of hepatitis B virus DNA from serum and histologic improvement was documented in 79% of the cases who had a control liver biopsy, while 15.8% developed cirrhosis. In two patients (4.9%), the disease remained active despite seroconversion, and both cases had evidence of continuing hepatitis B virus replication. Finally, reactivation of liver damage and of hepatitis B virus replication was observed in three additional patients (7.3%) who had transiently normalized SGPT after seroconversion. All 70 patients were analyzed for hepatitis delta virus markers, and only two persistently HBeAg-positive cases were found positive for antibody to hepatitis delta virus in serum, one also having hepatitis delta antigen in the liver. These findings indicate that, in chronic hepatitis type B, termination of virus replication is associated in most patients with biochemical and histologic regression of inflammatory activity. After anti-HBe seroconversion has occurred, virus replication and liver disease may persist or reactivate in a small proportion of patients thus giving origin to the well-recognized group of anti-HBe positive, hepatitis B virus DNA-positive chronic hepatitis type B.     

Comparison between quantitative hepatitis B surface antigen,hepatitis B e‐antigen and hepatitis B virus DNA levels for predicting virological response to pegylated interferon‐α‐2b therapy in hepatitis B e‐antigen‐positive chronic hepatitis B

Aim: The aim of this study was to compare the clinical applicability of quantitative serum hepatitis B surface antigen (HBsAg), hepatitis B e‐antigen (HBeAg) and hepatitis B virus (HBV) DNA for predicting virological response (VR) to pegylated interferon (PEG‐IFN) therapy. Methods: Thirty HBeAg‐positive chronic hepatitis B patients who received PEG‐IFN‐α‐2b for 48 weeks were enrolled. Quantitative HBsAg, HBeAg and HBV DNA were measured before, during and after the therapy. Paired liver biopsies were performed before and after treatment for covalently closed circular (ccc)DNA and intrahepatic HBV DNA analysis. Results: VR at 48 weeks post‐treatment, defined as HBeAg seroconversion and HBV DNA less than 10 000 copies/mL was achieved in 10 (33.3%) patients. Responders had significantly lower baseline HBsAg, HBeAg, cccDNA and intrahepatic HBV DNA levels than non‐responders. Baseline and reduced levels of log₁₀ HBsAg and log₁₀ HBeAg correlated well with those of log₁₀ cccDNA and log₁₀ total intrahepatic HBV DNA. Responders showed consistent decrease in serum HBsAg, HBeAg and HBV DNA levels during therapy. HBeAg level of 2.0 log₁₀ sample to cut‐off ratio at week 24 on therapy provided the best prediction of sustained virological response, with sensitivity and negative predictive values of 85% and 92%, respectively. One patient (3.3%) who cleared HBsAg at follow up exhibited a more rapid decline in serum HBsAg during therapy than those who developed VR without HBsAg clearance. Conclusion: Quantitative measurement of serum HBeAg during therapy may be superior to serum HBsAg and HBV DNA as a prediction of HBeAg seroconversion. Kinetics of HBsAg levels on therapy may help predict HBsAg clearance after treatment.     

Detection of pre-S1 proteins in serum and liver of HBsAg-positive patients: a new marker for hepatitis B virus infection

The presence of pre-S1 proteins in serum and liver of individuals with acute and chronic hepatitis B virus infection was investigated in Western blots using antibodies against a fusion protein, containing amino acids 20-120 of the pre-S region. Pre-S1 proteins were present in 20 of 38 HBsAg-positive sera. All sera positive for pre-S1 proteins were also positive for hepatitis B virus DNA indicating the presence of hepatitis B virions, and 16 of these sera were also positive for HBeAg. In five sera positive for hepatitis B virus DNA, pre-S1 proteins were not found. In an additional study, pre-S1 proteins could be detected in 4 of 6 patients with acute hepatitis B virus infection during the first 2 weeks after admission to the hospital. The presence of pre-S1 proteins showed a good correlation with the detection of hepatitis B virus DNA. After seroconversion from HBeAg to anti-HBe, both hepatitis B virus DNA and pre-S1 proteins were no longer detectable. Pre-S1 proteins were present in three liver tissue specimens from two patients with acute hepatitis B virus infection and from one patient with cirrhosis of the liver. The proteins were not found in the liver of two HBsAg-positive patients with hepatocellular carcinoma (primary liver carcinoma), negative for HBeAg. Pre-S1 proteins can be detected in serum, positive for hepatitis B virus DNA and in liver tissue of hepatitis B virus-infected individuals. The presence of these proteins appears to correspond with the presence of hepatitis B virus DNA, both markers indicating hepatitis B virus replication.     

Detection of proteins encoded by the pre-S region of hepatitis B virus in the sera of HBsAg carriers: relation to viral replication

In order to determine the relationship between the presence of pre-S1 and pre-S2 proteins and the level of hepatitis B virus (HBV) replication, a study of 94 HBsAg chronic carriers, 15 anti-HBe positive patients who suffered a viral reactivation and 12 HBeAg, HBV-DNA positive cases under antiviral therapy, has been carried out. Pre-S1 and pre-S2 antigens were detected by RIA using polystyrene beads coated with anti-preS1 or anti-preS2 (Dr W. Gerlich, G?ttingen) and 125I-anti-HBs as tracer. The presence of pre-S1 and pre-S2 antigens was detected in 74 (79%) and 85 (90%), respectively, out of the 94 HBsAg chronic carriers included. The level of these antigens was significantly higher in HBeAg, HBV-DNA positive patients than in the other patients (p less than 0.05). Among anti-HBe positive patients suffering a reactivation, a significant increase of pre-S1 and pre-S2 levels was observed, concurring with ALT exacerbation and HBV-DNA positivity. After reactivation, the level of pre-S antigens returned to the basal values. A significant decrease in pre-S antigen levels (p less than 0.05) among patients who respond to recombinant interferon therapy was observed, while no changes were detected among non-responder cases. The detection of pre-S1 and pre-S2 antigens in serum is more frequent in those patients with high viral replication. Furthermore, among anti-HBe carriers with a viral reactivation, synthesis of pre-S antigens takes place again.     

The effects of antiviral agents on serum hepatitis B e antigen levels in chronic type B hepatitis

In the present study, aiming at the evaluation of the effects of antiviral therapy on hepatitis B e antigen (HBeAg) levels, serum HBeAg concentration was determined serially by a quantitative assay in 44 patients with chronic hepatitis B who received a total of 73 courses of antiviral treatment. The posttreatment HBeAg levels were significantly lower than pretreatment baseline in all treated groups, not only at the end of treatment but also 6 months after the completion of therapy. The proportional decrease in treated patients was significantly greater than in 15 untreated controls. Six months after the completion of treatment, serum HBeAg became negative in seven out of 25 treatments with interferon, seven out of 28 with adenine arabinoside, and five out of 20 with adenine arabinoside 5'-monophosphate. All patients who became negative for HBeAg had normalization of alanine aminotransferase as well. A progressive decrease in HBeAg in patients treated with multiple courses of drug was observed, and the frequency of negative tests increased, paralleling the number of courses of treatment. These results suggest that antiviral therapy may alleviate inflammatory changes in the liver by promoting clearance of HBeAg from the serum, and may eventually shorten the natural course of hepatitis associated with chronic hepatitis B virus infection.