Clinical outcomes of chronic hepatitis B patients with persistently detectable serum hepatitis B virus DNA during lamivudine therapy

BACKGROUND AND AIM: A small proportion of chronic hepatitis B patients have persistently detectable serum hepatitis B virus (HBV) DNA despite lamivudine therapy. The incidence and clinical outcomes of patients who persistently have detectable serum HBV-DNA during lamivudine therapy was investigated. METHOD: We enrolled 221 chronic hepatitis B patients who underwent lamivudine therapy for more than 6 months. Among them, 180 were HBeAg positive. Serum HBV-DNA, HBeAg, anti-HBe and alanine aminotransferase (ALT) levels were serially monitored. The study groups were defined, using a hybridization assay, as patients with reductions in serum HBV-DNA below the detectable level (group I) or patients with persistently detectable serum HBV-DNA (group II) during the initial 6 months of lamivudine therapy. RESULTS: The incidence of patients who had persistently detectable HBV-DNA was 7.7%. After the first year, the rates of viral breakthrough, HBeAg loss and serum ALT normalization of group I versus group II were 21% versus 63%, 38% versus 0%, and 71% versus 28%, respectively (P < 0.001). The log(10) reduction of serum HBV-DNA at 6 months was -4.58 log(10) for group I and -1.97 log(10) for group II (P < 0.001, bDNA assay). There were no pretreatment lamivudine-resistant mutants in group II. CONCLUSION: Lamivudine had little effect on serum HBV-DNA suppression, viral breakthrough suppression and rate of HBeAg loss and ALT normalization in chronic hepatitis B patients with persistently detectable serum HBV-DNA during the initial 6 months of therapy. Early termination of lamivudine therapy is advocated for these patients.     

Hepatitis B virus precore mutations and HBeAg negative reactivation of chronic hepatitis B after interferon therapy

The objective of this study was to look for HBV precore mutations in three patients with chronic active hepatitis B who developed HBV-DNA-positive/HBeAg-negative reactivation after HBe seroconversion induced by interferon therapy. Direct sequencing of polymerase chain reaction products was performed on serum collected before and after HBe seroconversion. In two patients precore sequence showed only wild-type HBV before and after interferon therapy. In one patient, precore sequence showed only wild-type HBV before interferon therapy and a mixed infection by wild-type HBV and precore mutant viruses (1858 and 1896 nucleotide mutations) after treatment. The presence of HBeAg/anti-HBe immune complexes was found after HBe seroconversion in all cases. Our results suggest that: 1) precore mutations are not always found in patients with chronic hepatitis B who develop HBV DNA-positive/HBeAg-negative reactivation; and 2) HBeAg negativity, despite the presence of wild-type HBV, might be due to HBeAg/anti-HBe immune complexes. We speculate that the production of these immune complexes may be favored by interferon therapy.     

HBsAg定量检测对聚乙二醇干扰素治疗慢性乙型肝炎效果的预测价值

抗病毒治疗是慢性乙型肝炎(CHB)治疗的关键。聚乙二醇干扰素(PEG-IFN)兼有抗病毒和免疫调节作用,停药后可使30%~40%患者发生HBe Ag血清学转换实现持续病毒学应答。许多研究表明HBs Ag定量可作为PEG-IFN抗HBV疗效预测指标,以及停药后持久免疫控制的预测指标。综述了PEG-IFN在CHB抗病毒治疗前、治疗过程中及治疗结束时HBs Ag水平与抗病毒治疗的关系,以阐明HBs Ag定量监测对PEG-IFN治疗CHB的意义,更好的指导和调整抗病毒治疗方案。     

Lamivudine-high dose interferon combination therapy for chronic hepatitis B patients co-infected with the hepatitis D virus

Currently, the best option for patients with hepatitis delta is interferon alpha therapy for at least one year. To evaluate the effect of the combination lamivudine-high-dose interferon alpha therapy, we first treated eight patients with chronic hepatitis delta infection with lamivudine for at least 24 weeks; then lamivudine was combined with a high dose of interferon alpha followed by a regular dose (9 MU tiw). Follow-up was 12 weeks. Virological, biochemical and histological features were evaluated for response to therapy. At baseline, all patients were HBsAg positive in serum and HDV RNA-(PCR)positive in plasma; HBV DNA was undetectable with the Digene Hybrid Capture assay (limit of detection 1.5 x 10(6) geq ml-(1)) in all cases. Transaminases were elevated in all patients; median ALT 68 (range 48-143) IU l(1). Seven of eight patients completed the course; one patient with a pre-existing sickle cell trait was withdrawn from the trial due to the development of a nephrotic syndrome. The HBsAg-concentration in serum decreased in two out of seven patients (29%). However, there was no significant decrease in the HBsAg-concentration in serum during treatment (median 3654 PEU l(-1) (range 548-7,684) to 5300 PEU l(-1) (range 168-19,639)). The drop of HDV RNA in plasma from baseline during treatment was not significant. Decrease of HDV RNA was observed in three out of seven patients (43%) (median 10(5) geq ml(-1); range 10(3)-10(6) to median 10(3) geq ml(-1); range 10(2)-10(7)). Serum ALT did not change as reflected by a median of 68 IU l(-1) (range 48-143) at start of therapy to 63 IU l(-1) (range 20-171) at the end of therapy. At the end of treatment transaminases had normalised in one patient and decreased in three other patients (improvement in 57%). However, three of these four patients showed a rebound after withdrawal of therapy. The Histology Activity Index (HAI) indicated a drop from a median score of 7 (range 5-9) at baseline to 5 (range 3-8) at the end of treatment, but an increase in fibrosis from a median grade of 2 (range 1-3) at baseline to 3 (range 1-4) at the end of treatment was observed. In conclusion, this study does not yield support for the combination of an HBV suppressor and 16 weeks of high-dose interferon for therapy aimed at eradicating the hepatitis delta virus.     

Development of transient autoimmune hepatitis during interferon treatment of chronic hepatitis B

Summary A 42-year-old man was treated with interferon- for chronic hepatitis B; during the fourth week of treatment he developed an exacerbation of liver disease, and nuclear and smooth muscle autoantibodies, which were previously negative, were detected in very high titers. After discontinuation of interferon therapy, ALT values subsided promptly and autoantibodies disappeared within a few months. This sequence of events strongly suggests a direct relationship between IFN treatment and a self-limited hepatitis with autoimmune markers in this case.     

ALT轻度升高、HBVDNA水平不同的慢性乙型肝炎患者肝组织学差异探讨

肝炎,乙型,慢性;;丙氨酸转氨酶;;肝炎病毒,乙型;;DNA,病毒 %X 目的探讨ALT轻度升高的慢性乙型肝炎（CHB）患者ALT正常值上限二倍上下的肝脏组织学改变有无差异,以解决ALT〈80 U/L的ALT轻度升高的CHB患者抗病毒治疗问题。方法将HBeAg阳性和阴性的两种ALT轻度升高的CHB患者120例,按不同HBV DNA水平分组,再以ALT正常值上限的二倍（80 U/L）分为ALT≥80 U/L和ALT〈80 U/L两组进行肝组织学研究。行肝脏穿刺和病理检查,比较不同HBV DNA水平分组（各分为ALT≥80 U/L和〈80 U/L两组）的肝组织学改变有无差异。结果 HBeAg阳性和阴性两种ALT轻度升高的CHB患者（ALT〈80 U/L与≥80 U/L两组）的不同HBV DNA水平分组的组织学改变情况,两组肝脏的炎症活动度和纤维化分期差异均无统计学意义（P〉0.05）。结论经比较HBeAg阳性或阴性两种ALT轻度升高的CHB患者的不同HBV DNA水平分组的肝组织学改变情况显示,ALT≥80 U/L和〈80 U/L两组CHB患者的肝脏组织学改变差异均无统计学意义,为ALT〈80 U/L的ALT轻度升高的CHB患者,寻求抗病毒治疗的依据进行了有益的探讨。     

Are alanine aminotransferase,hepatitis B virus DNA or IgM antibody to hepatitis B core antigen serum levels predictors of histological grading in chronic hepatitis B?

Abstract: Paired sera and liver biopsies from 105 patients with chronic hepatitis B virus infection (34 HBeAg positive and 71 anti-HBe positive) were studied to investigate the relation between the degree of histological activity and alanine aminotransferase (ALT), hepatitis B virus DNA (HBV-DNA) or IgM antibody to hepatitis B core antigen (IgM anti-HBc) levels. ALT levels were significantly higher in patients with piecemeal necrosis (155±124 vs 75±42, p=0.0017), but there were no differences in the ALT values of patients with or without intralobular necrosis. ALT values were within normal range in 29% of 31 patients without versus 15% of 65 with piecemeal necrosis (p=0.19). Serum HBV-DNA levels were not related to the grade of lobular or portal/periportal activity in HBeAg-positive patients. Anti-HBe-positive subjects with piecemeal necrosis had higher HBV-DNA levels (34±93 vs 4±6, p=0.01). IgM anti-HBc indexes were significantly higher in patients with intralobular necrosis (0.635±0.600 vs 0.356±0.367, p=0.0005) or piecemeal necrosis (0.671 ±0.633 vs 0.321 ±0.219, p=0.0002). In summary, since serum IgM anti-HBc-IMx indexes can reflect the grade of histological activity, the quantitative assessement of this antibody could be useful for non-invasive monitoring of hepatocellular damage in chronic hepatitis B.     

Lack of association between occult hepatitis B virus DNA viral load and aminotransferase levels in patients with hepatitis C virus-related chronic liver disease

BACKGROUND AND AIM: Occult hepatitis B virus (HBV) infection in hepatitis C virus (HCV)-infected patients might enhance the severity of chronic liver disease (CLD). To elucidate the correlation between occult HBV infection and the clinical course of HCV-related CLD, we evaluated whether the fluctuation of occult HBV-DNA directly affects the serum alanine aminotransferase (ALT) level. METHODS: Forty-one patients with HCV-related CLD who received regular outpatient treatment and 42 age-, sex-, and antibody to hepatitis B core antigen positivity-matched healthy volunteers were enrolled. Serum HBV-DNA was quantitatively detected using real-time detection polymerase chain reaction (RTD-PCR). Serial serum samples in three patients were measured for HBV-DNA, ALT and HCV core antigen. RESULTS: Hepatitis B virus DNA was amplified in eight of the HCV-related CLD patients (19.5%), which was significantly higher than that of healthy volunteers (2.4%). No significant difference between the genotype 1 HCV-related CLD group and the genotype 2 group was found. Based on the analyses using serial serum samples, the elevation of HBV-DNA did not occur before the ALT flares, but occurred at the same time or after the ALT flares. CONCLUSIONS: The prevalence of occult HBV infection of HCV-related CLD is significantly higher than that of control. Occult HBV infection has no influence on ALT flares among patients with HCV-related CLD.     

Appropriate use of interferon for treatment of chronic hepatitis B

Hepatitis B is not only a preventable but now treatable disease. Five drugs have been approved for the treatment of chronic hepatitis B virus (HBV) infection: standard interferon-α (IFN), pegylated IFN, lamivudine, adefovir dipivoxil and entecavir. Among these agents, the responses to interferon therapy are invariably influenced by both host and viral factors. Therefore, understanding these factors is important for practicing hepatologists, and it may help design individualized medicine for the treatment of chronic hepatitis B. HBV genotypes affect the disease progression and outcomes of HBV-related chronic liver disease, as well as the response to antiviral treatments. Existing data indicate a better sustained response to standard IFN-α in HBeAg positive genotype B patients than genotype C patients, and in genotype A patients than genotype D patients. Nevertheless, conflicting results exist regarding the response to pegylated IFN, and more studies are needed. As to HBV genetic polymorphisms, a recent study showed that an IFN sensitivity-determiningregion may not exist within the whole genome of HBV subgenotype Ba, and host factors as well as virus–host interactions may be more important than viral factors alone in determining the treatment outcomes with IFN. Regarding host genetic polymorphisms, single nucleotide polymorphisms within eukaryotic translation initiation factor 2 and MxA promoter regions may be associated with the responsiveness to standard IFN-α treatment in patients with HBeAg positive chronic hepatitis B. In the foreseeable future, individualized chronic hepatitis B treatment algorithms should be tailored to host (immune status, ALT level and genomic polymorphisms), virus (HBeAg status, HBV DNA level, genotype, precore/basal core promoter mutants and pre-S deletion mutant) as well as liver disease status (hepatitis activity and fibrosis stage).     

Clinical significance of SEN-virus on interferon response in chronic hepatitis C patients

BACKGROUND AND AIM: A novel virus, SEN-virus (SENV), was recently discovered. It has been reported as a candidate for a non-A-E hepatitis virus. However, much is still unknown about the clinical significance of SENV. The aim of the present study was to clarify the clinical significance of SENV in patients coinfected with SENV and hepatitis C virus (HCV). METHODS: The 52 subjects had chronic hepatitis C and had undergone interferon (IFN) therapy. SEN virus DNA was investigated by using polymerase chain reaction with SENV-specific primers, which we designed to detect all strains of SENV. Additionally, SENV-D and -H were detected by consensus primers. RESULTS: Thirty-five patients were SENV-DNA positive and 22 patients were SENV-D- or -H-positive before IFN therapy. After IFN therapy, in the HCV-RNA eradication group, all cases normalized their serum alanine aminotransferase (ALT). However, in the no eradication group, the ALT no-response rate was 68.7%. In contrast, in the SENV eradication group, the ALT no-response rate was 51.9%, and in the no eradication group, it was 37.5%. Also, in the SENV-D and -H eradication group, the ALT no-response rate was 54.5%, and in the no eradication group, it was 36.4%. The changes in ALT after IFN therapy were significantly correlated with the changes in HCV RNA, but no correlation was found with the SENV DNA presence. CONCLUSIONS: Hepatocellular injury in patients with chronic hepatitis who are coinfected with HCV and SENV appears to primarily be caused by HCV, and is less attributable to SENV.     

Effect of multiple mutations in the core promoter and pre-core/core region of hepatitis B virus genome on the response to interferon in e antigen-positive chronic hepatitis B

BACKGROUND AND AIMS: Hepatitis B virus (HBV) genomic mutations may be one of the factors that influence the efficacy of interferon (IFN) therapy. The aim of this study was to investigate the effects of mutations in different parts of the HBV genome on IFN therapy. METHODS: We studied the baseline clinical, biochemical, serologic and virologic parameters in 17 patients with e antigen-positive chronic hepatitis B. The DNA sequence of the X gene and pre-core/core gene in serum samples of these patients was analyzed before the initiation of IFN therapy. RESULTS: All five patients with the T1762-A1764 mutation were IFN responsive, while among the 12 remaining patients, only two responded to therapy. Among five patients with both a pre-core A1896 mutation and a mutation in the epitope aa 107-118 of the core region, four were non-responders whereas the fifth responded to therapy. In three other patients with A1896 mutations, one with simultaneous mutations in five lymphocytic epitopes did not respond to therapy; the two remaining patients with concomitant mutations in one or two epitopes were responsive. Serum HBV-DNA levels were lower and titers of antibody to hepatitis B virus core antigen-immunoglobin M (anti-HBc-IgM) were higher in the responders than in the non-responders. Hepatitis B virus genotypes B and C were found to be in all these Chinese patients. CONCLUSIONS: These results suggest that HBV genomic mutations, serum viral loads and titers of anti-HBc-IgM might be predictive of the efficacy of IFN therapy. These clinical findings should be further investigated by in vivo and in vitro experiments.     

Relationship between hepatitis B virus DNA levels and liver histology in patients with chronic hepatitis B

AIM： To study the relationship between hepatitis B virus （HBV） DNA levels and liver histology in patients with chronic hepatitis B （CHB） and to determine the prevalence and characteristics of hepatitis B e antigen （HBeAg） negative patients.
METHODS： A total of 213 patients with CHB were studied, and serum HBV DNA levels were measured by the COBAS Amplicor HBV Monitor test. All patients were divided into two groups according to the HBeAg status.The correlation between serum HBV DNA levels and liver damage （liver histology and biochemistry） was explored.
RESULTS： Of the 213 patients with serum HBV DNA levels higher than 10^5 copies/mL, 178 （83.6%） were HBeAg positive, 35 （16.4%） were HBeAg negative. The serum HBV DNA levels were not correlated to the age,history of CHB, histological grade and stage of liver disease in either HBeAg negative or HBeAg positive patients. There was no correlation between serum levels of HBV DNA and alanine aminotransferanse （ALT）,aspartate aminotrans-ferase （AST） in HBeAg positive patients. In HBeAg negative patients, there was no correlation between serum levels of HBV DNA and AST,while serum DNA levels correlated with ALT （r = 0.351, P = 0.042）. The grade （G） of liver disease correlated with ALT and AST （P 〈 0.05, r = 0.205, 0.327 respectively）in HBeAg positive patients. In HBeAg negative patients,correlations were shown between ALT, AST and the G （P 〈 0.01, and r = 0.862, 0.802 respectively）. HBeAg negative patients were older （35 ± 9 years vs 30 ±9 years, P 〈 0.05 ） and had a longer history of HBV infection （8 ± 4 years vs 6 ± 4 years, P 〈 0.05） and a lower HBV DNA level than HBeAg positive patients （8.4± 1.7 Log HBV DNA vs 9.8 ± 1.3 Log HBV DNA, P 〈0.001）. There were no significant differences in sex ratio,ALT and AST levels and liver histology between the two groups.
CONCLUSION： Serum HBV DNA level is not correlated to histological grade or stage of liver disease in CHB patients with HBV DNA mor     

Changes of serum aminotransferase activities in relation to serum hepatitis Be antigen levels in chronic type B hepatitis

The purpose of this study was to determine the level of serum hepatitis Be antigen (HBeAg) during hepatitis B virus carriage and its clinical significance. The mean level of serum HBeAg, quantitated by solid-phase enzyme immunoassay, was 5924 units in asymptomatic carriers (s.d. = 5534, n= 100), 3044 units in patients with chronic persistent hepatitis (s.d. = 4826, n= 34), 3599 units in chronic active hepatitis (s.d. = 4953, n= 45) 1348 units in liver cirrhosis (s.d. = 2379, n= 25) and 766 units in hepatocellular carcinoma (s.d. = 1257, n= 18). In the 10 HBeAg-positive patients with chronic active hepatitis, the fluctuation in HBeAg level was followed by changes in alanine aminotransferase (ALT) activity. Among the 36 peaks of HBeAg and ALT, HBeAg peaks preceded ALT peaks in 22 and simultaneous peaks were present in 14. The changes of HBeAg level were closely related to increase in disease activity as estimated by ALT activities; therefore, HBeAg quantitation can be a useful predictor of disease activity in chronic hepatitis B.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Alanine aminotransferase and HCV-RNA responses following interferon therapy of HCV-RNA positive chronic hepatitis

Interferon (IFN) has been shown to be effective for chronic hepatitis C. This study investigated changes of alanine aminotransferase (ALT) and HCV-RNA in chronic hepatitis C patients treated withα-IFN. IFN was given to 73 patients with HCV-RNA positive chronic hepatitis C. The pattern of changes in ALT activity after IFN aministration was classified into five types. Type 1 was characterized by normalization of ALT (≤25 K.U) during IFN administration and sustained normalization after the IFN therapy. Type 2 involved a rebound of ALT after termination of IFN therapy and subsequent normalization. Type 3 had no ALT normalization during IFN administration, with normalization after the completion of the therapy. Type 4 involved transient normalization of ALT level during IFN therapy, with a subsequent reversion to abnormal levels after the termination of IFN therapy. Type 5 showed sustained abnormally high levels of ALT activity both during and after treatment. Twenty four patients (32.9%) had sustained normalization ALT (≤25 K.U) after the termination of IFN treatment. The HCV-RNA negative rate at 6 months after IFN therapy in patients with sustained normalization of ALT was 87.5% (21/24).     

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.     

Cyclosporine therapy affects aminotransferase activity but not hepatitis C virus RNA levels in chronic hepatitis C

Interferon (IFN) therapy is of proven efficacy in chronic hepatitis C, but it is not universally effective and is often limited by side effects. Cyclosporine A (CsA) is a potent immunosuppressant widely used in organ transplantation. We conducted a pilot study to determine whether CsA therapy could affect aminotransferase activity and hepatitis C virus RNA levels in patients with chronic hepatitis C. Cyclosporine A was administered to 10 patients (mean age of 59 years; male: female = 9:1) who did not respond to IFN therapy previously and who had elevated serum alanine aminotransferase (ALT) values for at least 6 months. All patients were positive for HCV-RNA by RT-PCR with genotype 1b. Their mean duration of hepatitis was 15 years. Oral CsA was given for 3 months in a dose that was increased at 1 month intervals from 1.5–2.0 to 2.0–3.0 and 3.0–4.0 mg/kg per day. All patients completed the treatment schedule, although two patients developed mild non-symptomatic hypertension. Serum ALT levels gradually decreased in all but one patient. The mean percentage decrease was 59.5% at the end of therapy (from 153 ± 82 to 62 ± 48 IU/L; P < 0.02). The ALT levels fell to the normal range in five patients, although once therapy was discontinued the enzyme levels tended to return to pretreatment levels. Serum aspartate aminotransferase and g-glutamyl transpeptidase levels similarly decreased. The serum HCV-RNA titre, determined by competitive RT-PCR, did not change in any patient throughout the study period. There were no appreciable alterations in other laboratory tests, such as serum creatinine levels and lymphocyte subsets, except for an increase in serum alkaline phosphatase levels. These findings suggest that CsA, even in a relatively low dose, reduces serum aminotransferase levels without serious side effects in patients with chronic-hepatitis C, although an antiviral effect was not noted.     

Discriminant value of serum HBV DNA levels as predictors of liver fibrosis in chronic hepatitis B

Summary. Current guidelines recommend antiviral therapy in chronic hepatitis B (HBV) patients with significant histological disease. We aimed to compare histological fibrosis (METAVIR, ≥F2) in patients with HBV DNA ≥20 000 IU/mL vs≥2000 IU/mL and identify predictors of fibrosis. We performed prospective liver biopsies on 203 HBeAg‐negative patients in four groups: Group I (n = 55): HBV DNA ≥20 000 IU/mL and persistently elevated alanine aminotransferase (ALT) levels (PEALT; >40 U/L); Group II (n = 34): HBV DNA ≥20 000 IU/mL and persistently normal ALT (PNALT); Group III (n = 40): HBV DNA <20 000 IU/mL and PEALT; and Group IV (n = 74): HBV DNA <20 000 IU/mL, and PNALT. We reanalysed all groups in relation to updated cut‐off for treatable viremia (2000 IU/mL). Genotype D was detected in 86% of patients. Hepatic fibrosis ≥F2 was detected in 72.7%, 52.9%, 57.5% and 18.9% in Groups I–IV, respectively (P < 0.0001). Except in Group II with a trend for lower ≥F2 fibrosis (P = 0.067), there was no significant difference by using HBV DNA cut‐off 20 000 vs 2000 IU/mL. Multivariate logistic regression analysis identified study Group IV (OR, 0.0276; CI: 0.088–0.868; P = 0.0276) and milder (A0–1) necroinflammatory grade (OR, 0.135; CI: 0.063–0.287; P < 0.0001) as independent predictors of ≥F2 fibrosis. The specificity, positive and negative predictive values for PEALT in detection of ≥F2 fibrosis for viremia ≥2000 IU/mL (80%, 69% and 65%, respectively) or ≥20 000 IU/mL (86%, 73% and 63%, respectively) were similar, with a marginal gain in sensitivity (51%vs 42%, respectively). Significant fibrosis is prevalent in a large proportion of HBeAg‐negative patients with high viremia and persistently normal ALT. Lower HBV DNA cut‐offs could be adopted with marginal gains in fibrosis detection and without loss of diagnostic accuracy.