The HBV DNA cutoff value for discriminating patients with HBeAgnegative chronic hepatitis B from inactive carriers

Background

Patients with HBeAg-negative chronic hepatitis B (CHB) has a significantly different prognosis than inactive carriers; there is however, no reliable strategy for accurately differentiating these two disease conditions.

Objectives

To determine a strategy for discriminating patients with HBeAg-negative CHB from inactive carriers.

Materials and Methods

Consecutive inactive carriers (i.e. HBeAg-negativity, anti-HBe-positivity, normal ALT levels, and HBV DNA < 2000 IU/mL) were enrolled. HBV reactivation was defined as the elevation of the HBV DNA level to ≥ 2000 IU/mL. Patients were classified into true inactive carriers when their HBV DNA levels remained at < 2000 IU/mL or false inactive carriers when their HBV DNA levels increased to ≥ 2000 IU/mL during the first year.

Results

The Mean ± SD age of 208 inactive carriers (140 males) was 47.7 ± 12.6 years. The Mean ± SD serum ALT and HBV DNA levels were 22.8 ± 8.6 IU/L and 360 ± 482 IU/mL, respectively. HBV reactivation developed in 41 (19.7%) patients during the first year. Baseline HBV DNA and ALT levels differed significantly between true inactive and false inactive carriers. The AUROCs of the baseline ALT and HBV DNA levels for predicting a false inactive carrier were 0.609 and 0.831, respectively. HBV reactivation developed more often in patients with a baseline HBV DNA level of ≥ 200 IU/mL than in those with a baseline HBV DNA level of < 200 IU/mL during a Mean ± SD follow-up of 622 ± 199 days.

Conclusions

The HBV DNA level was useful for discriminating patients with HBeAg-negative CHB from true inactive carriers. The follow-up strategies applied to inactive carriers need to vary with their HBV DNA levels.     

Lower baseline ALT cut-off values and HBV DNA levels better differentiate HBeAg（-） chronic hepatitis B patients from inactive chronic carriers

AIM： To determine whether new cut-off values for aianine aminotransferase （ALT） and baseline hepatitis B virus （HBV） DNA levels better differentiate HBeAg（-） chronic hepatitis B （CriB） patients from inactive chronic carriers.
METHODS： Ninety-one patients [32 HBeAg（＋） CriB, 19 inactive carriers and 40 HBeAg（-） CriB] were followed up for 2 years and were tested for HBV DNA levels by a PCR-based assay. ALT was tested twice during the last 6 mo using new cut-off values： ULN （upper limit of normal） 30 IU/L for males, 19 IU/L for females. Diagnostic accuracy, sensitivity, specificity, positive and negative predictive values were calculated by discriminant analysis.
RESULTS： When using the revised ALT cut-off values, the lowest optimal HBV DNA level that differentiated HBeAg（-） CHB patients from inactive carriers was 50000 copies/mL. The diagnostic accuracy of HBV DNA to determine inactive carriers with a cut-off of 50000 copies/mL was similar to the previously recommended cut-off of 100000 copies/mL （91%）. HBV DNA levels were lower than the cut-off value in 95% of inactive carriers and in 28% of HBeAg（-） CHB patients. With ALT 〈 30 IU/L in men and 〈 19 IU/L in women and HBV DNA levels 〈 100000 copies/mL, the risk of CHB is 5%. On the other hand, if ALT values were 〉 30 IU in men and 〉 19 IU in women and baseline HBV DNA levels were 〉 100000 copies/mL, the risk is 86%.
CONCLUSION： New cut-off values for ALT together with HBV DNA levels proposed by AASLD （American Association for the Study of Liver Diseases） and NIH （National Institute of Health） consensus seem appropriate to characterize inactive carriers.     

Is there a meaningful serum hepatitis B virus DNA cutoff level for therapeutic decisions in hepatitis B e antigen-negative chronic hepatitis B virus infection?

The diagnosis of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B indicating therapeutic intervention currently requires serum hepatitis B virus (HBV) DNA >or=2,000 IU/mL. We evaluated the severity of liver histology and the presence of histological indication for treatment in patients with HBeAg-negative chronic HBV infection focusing on those with low viremia and/or normal alanine aminotransferase (ALT). In total, 399 patients with increased ALT and detectable serum HBV DNA (chronic hepatitis B patients) and 35 cases with persistently normal ALT and HBV DNA >2,000 IU/mL (inactive carriers) were included. Histological indication for treatment (grading score >or=7 and/or stage >or=2 in Ishak's classification) was found in 91% (185/203), 82% (75/91), 75% (47/63), and 62% (26/42) of chronic hepatitis B patients with HBV DNA >or=200,000, 20,000-199,999, 2,000-19,999, and <2,000 IU/mL, respectively (P < 0.001). Histological indication for treatment was more frequent in chronic hepatitis B patients with persistently elevated ALT (86% or 275/321), but it was also found in 74% (58/78) of those with transiently normal ALT (P = 0.025). All inactive carriers had HBV DNA <20,000 IU/mL. Histological indication for treatment was present in 17% (6/35) of inactive carriers always due to moderate (stage 2) fibrosis without active necroinflammation. CONCLUSION: HBeAg-negative chronic HBV patients with persistently or transiently increased ALT and HBV DNA >or=20,000 IU/mL almost always require therapeutic intervention, but histological indications for treatment are also present in the majority of such cases with HBV DNA <20,000 and even <2,000 IU/mL. In contrast, minimal histological lesions are observed in the majority of HBeAg-negative patients with persistently normal ALT and HBV DNA >2,000 IU/mL, who may not require immediate liver biopsy and treatment but only close follow-up.     

Efficacy and safety of entecavir in lamivudine-refractory patients with chronic hepatitis B: randomized controlled trial in Japanese patients

Background and Aim:  Entecavir is a potent inhibitor of both wild-type and lamivudine-resistant hepatitis B virus (HBV) with proven clinical efficacy. We conducted a randomized, double-blind, multicenter study in Japan (ETV-052) evaluating the efficacy and safety of two doses of entecavir in adult patients with lamivudine-refractory chronic hepatitis B infection.
Methods:  Eighty-four patients with chronic hepatitis B who were refractory to lamivudine therapy were switched from lamivudine to daily oral doses of 0.5 mg entecavir (41 patients) or 1 mg entecavir (43 patients) for 52 weeks.
Results:  The proportions of patients achieving the primary end-point (≥2 log₁₀ reduction in HBV-DNA from baseline by polymerase chain reaction assay or undetectable HBV-DNA levels [<400 copies/mL] at week 48) were 90% and 93% for entecavir 0.5 mg and 1 mg, respectively, with 33% of patients in each dosing group achieving <400 copies/mL. The mean reduction in HBV-DNA from baseline was 3.58 and 3.75 log₁₀ copies/mL for entecavir 0.5 mg and 1 mg, respectively. High proportions of patients achieved alanine aminotransferase normalization at week 48 (0.5 mg 86%, 1 mg 78%). Histological improvement was observed in most patients (0.5 mg 52%, 1 mg 60%). Virological breakthrough (increase in HBV-DNA of ≥1 log₁₀ copies/mL from nadir) was observed in one patient but was not associated with selection of entecavir-associated resistance substitutions. Entecavir was well tolerated, with no patients discontinuing study drug due to adverse events.
Conclusions:  These findings indicate that entecavir is safe and effective for the treatment of Japanese adults with lamivudine-refractory chronic hepatitis B.     

The natural history of chronic hepatitis B

Summary.  The natural history of chronic hepatitis B is dependent on the age of acquiring the hepatitis B infection. Those who are infected at adolescence or adulthood (including most of the Caucasians) tend to have stable disease after hepatitis B e antigen seroconversion with normal serum alanine aminotransaminase (ALT) and hepatitis B virus (HBV) DNA levels <10⁵ copies/mL (20 000 IU/mL). In contrast, those who are infected at birth or early childhood (including the majority of the world's hepatitis B carriers, i.e. Asians) have a prolonged immune tolerance phase followed by a prolonged immune clearance phase. A proportion of these patients have progressive disease after HBeAg seroconversion with HBV DNA <10⁴ copies/mL (<2000 IU/mL) and ALT between 0.5 and 2× upper limit of normal. Core promoter mutations may play a part in the development of cirrhosis-related complications. However, continuing viral replication, even at a relatively low level of <10⁴ copies/mL (<2000 IU/mL), is probably the most important factor for the development of complications.     

Efficacy and safety of entecavir in nucleoside-naive, chronic hepatitis B patients: Phase II clinical study in Japan

Background and Aim:  Entecavir has demonstrated clinical efficacy for chronic hepatitis B. This study evaluated the efficacy and safety of entecavir in nucleoside-naive Japanese chronic hepatitis B patients.
Methods:  In this multicenter, double-blind study, 66 nucleoside-naive Japanese chronic hepatitis B patients were randomized to 0.1 mg entecavir ( n  = 32) or 0.5 mg entecavir ( n  = 34) daily for 52 weeks. The primary endpoint was the proportion of patients whose serum hepatitis B virus (HBV) DNA decreased from baseline by ≥2 log₁₀ copies/mL or became undetectable (<400 copies/mL by polymerase chain reaction assay) at week 48.
Results:  One hundred percent of patients in both treatment groups achieved the primary efficacy endpoint, with 81% and 68% of patients achieving undetectable HBV DNA in the 0.1 mg and 0.5 mg treatment groups, respectively. Mean changes from baseline in HBV DNA were −4.49 log₁₀ and −4.84 log₁₀ copies/mL for the 0.1 mg and 0.5 mg groups, respectively. Significant improvements in necroinflammation were seen in both groups, as assessed by Knodell and New Inuyama classifications. Most adverse events were transient and classified as grade 1 or 2. There were no clinically significant differences in adverse events across the two treatment groups and no discontinuations due to adverse events in either group.
Conclusions:  In Japanese nucleoside-naive patients with chronic hepatitis B, 0.1 mg or 0.5 mg entecavir daily provided excellent efficacy and was well tolerated. The 0.5 mg dose was selected for the treatment of nucleoside-naive patients.     

Naturally occurring amino–acid substitutions to nucleos(t)ide analogues in treatment naive Turkish patients with chronic hepatitis B

Summary.  Naturally occurring amino-acid substitutions in the hepatitis B virus (HBV) polymerase gene may be responsible for resistance to nucleoside/nucleotide (NUCs) analogues. To date, only pre-existing lamivudine resistance has been extensively studied. The aim of the present study was to determine the naturally occurring or pre-existing amino-acid substitutions related to NUCs in treatment naive Turkish patients with chronic hepatitis B (CHB). The investigation involved a total of 88 patients (65 males and 23 females; mean age, 34 years; range, 15–61 years) who were diagnosed with CHB between April 2008 and January 2009. According to HBeAg status, 66 patients were HBeAg-negative and 22 patients were HBeAg positive. Naturally occurring substitutions in the HBV polymerase region were detected by DNA sequencing in 17 (19%) and 30 (34%) patients, based on manual and geno2pheno tool database interpretation, respectively. Each amino-acid substitution appeared alone and included rtA194T, rtV214A, rtQ215S, rtI233V and rtN236T. The median values for viral load, ALT and AST were 3.3 log₁₀ (2.0–6.0) IU/mL, 36 (12–515) U/L and 27 (13–284) U/L, respectively, but these did not correlate with the observed amino-acid substitutions in the polymerase region. By direct sequencing, genotype D of HBV was found to still be dominant among Turkish patients. In conclusion, every patient who is diagnosed with CHB should be monitored before the start of treatment for more effective management of patient treatment options.     

Evaluation of initial virological response to adefovir and development of adefovir-resistant mutations in patients with chronic hepatitis B

Summary.  The aims of the present study were to assess initial virological response (IVR) to adefovir (ADV) treatment for chronic hepatitis B, to identify patients with suboptimal response and to determine the incidence of ADV-resistant mutants. All patients treated with ADV for at least 12 months were evaluated for virological response and ADV resistance. IVR was defined as a reduction ≥4 log₁₀ IU/mL in hepatitis B virus (HBV)-DNA at month 6. Forty-two patients were analysed. Mean treatment duration was 23 ± 7 months; 50% had prior lamivudine (LAM) therapy (LAM resistance 62%); 88% were hepatitis B e antigen (HBeAg)-negative; and 76% carried genotype D. IVR was seen in 40.5% of patients. Higher baseline ALT level was the only factor associated with IVR ( P  = 0.043). Patients with IVR achieved undetectable HBV-DNA at month 12 in 77% of cases compared with only 5% of those without IVR ( P  < 0.001). Five (12%) patients developed ADV-resistant mutations: rtN236T in four cases and one case with an rtV207L change, which has not been previously reported. This mutation was accompanied by viral rebound and alanine aminotransferase (ALT) flare. The cumulative probability of ADV-resistant mutations at 12 and 24 months was 5% and 17% respectively. IVR defined as a reduction ≥4 log₁₀ IU/mL in HBV-DNA at month 6 is a useful tool to predict virological response at month 12 and to identify patients with suboptimal response to ADV. Cumulative probability of ADV resistance is higher than previously reported for nucleos(t)ide-naïve patients.     

Hepatitis B virus DNA prediction rules for hepatitis B e antigen-negative chronic hepatitis B

After hepatitis B e antigen (HBeAg) seroconversion, hepatitis B may become inactive or progress to HBeAg-negative hepatitis with persistent or intermittent alanine aminotransferase (ALT) elevation. The aim of this study was to prospectively identify factors predictive of the clinical course in HBeAg-negative chronic hepatitis B (CHB). Patients were stratified by ALT and HBeAg status and followed every 3 months for up to 5 years. Kaplan-Meier and Cox regression analysis using the change from normal ALT to elevated ALT as endpoints were performed to determine factors associated with ALT elevation/normalization. Seventy-four HBeAg-negative and 32 HBeAg-positive patients were prospectively evaluated. For HBeAg-negative patients, hepatitis B virus (HBV) DNA was predictive of future ALT. Only 1 patient with normal ALT and an HBV DNA value lower than 10,000 copies/mL developed an elevated ALT within the subsequent year, whereas 67% with an HBV DNA value greater than 100,000 copies/mL had a rise in ALT above normal within 1 year. Patients with a previous history of ALT elevation and longer follow-up at all levels of HBV DNA were more likely to experience ALT elevations. For HBeAg-negative patients with elevated ALT and all HBeAg-positive patients, HBV DNA did not predict future ALT. Other viral and host factors were not predictive of future ALT. CONCLUSION: HBeAg-negative CHB has a fluctuating course. HBV DNA values lower than 10,000 copies/mL predict persistently normal ALT for at least 1 year. Patients with HBV DNA values between 10,000 and 100,000 copies/mL can safely be followed at 6 monthly intervals, whereas HBV DNA values greater than 100,000 copies/mL are highly predictive of future ALT elevation and should prompt regular follow-up.     

Reduced glomerular filtration rate but sustained virologic response in HIV/hepatitis B co-infected individuals on long-term tenofovir

Summary.  Reports have described a decrease in glomerular filtration rate (eGFR) associated with tenofovir disoproxil fumarate (TDF) use in HIV positive individuals. However, no study has examined renal function over a prolonged period in HIV/hepatitis B virus (HBV) co-infected patients. We assessed the long-term durability and toxicity of TDF in a cohort of 39 e antigen (eAg) positive co-infected patients commenced on TDF 245 mg daily either in addition to or as part of standard antiretroviral therapy. Immunological and virological parameters were followed to 260 weeks, with the median follow-up period being 251 weeks (range 69–290 weeks). eGFR was calculated using the Modification in Diet in Renal Disease equation. On treatment at 260 weeks, 88% (14/16) had HIV viral load <50 copies/mL, median CD4 count rose from 318 to 532 cells/mm³, median alanine aminotransferase (ALT) fell from 61 IU/L to 42 IU/L, with 35% (7/20) having a normal ALT, median HBV DNA fell from 69 × 10⁶ copies/mL to 500 copies/mL, with 75% (12/16) having an undetectable HBV DNA level and 55% (6/11) becoming eAg negative. Of those with detectable HBV DNA, none had TDF resistance mutations. The eGFR declined by 22.19 mL/min/1.73 mm² from baseline ( P  =   0.023) over this period, which was unaffected by protease inhibitor use, baseline CD4 count, ALT or HBV DNA level. Three patients discontinued TDF therapy due to renal dysfunction. In conclusion, TDF has sustained efficacy but is associated with a significant decline in eGFR. Further larger studies are required to clarify this observation.     

Tenofovir in the Treatment of Na?ve and Refractory Chronic Hepatitis B: A Single Center Experience in Saudi Arabia

Background/Aims:

Tenofovir disoproxil fumarate (TDF) is a nucleotide analog used in the treatment of chronic hepatitis B (CHB) infection. This study evaluated the efficacy of TDF in achieving undetectable HBV DNA after 48 weeks of treatment in a Saudi cohort of CHB patients.

Patients and Methods:

This retrospective study included patients treated at a tertiary care center in Saudi Arabia from January 2009 to December 2012. Of the 68 eligible patients, 51 were treatment naïve and 17 were treatment-refractory. Twenty-three patients tested positive for HBeAg. The remaining 45 patients were HBeAg-negative.

Results:

The mean HBV DNA viral load decreased from 95 million IU/mL at baseline to 263 IU/mL after 48 weeks of treatment (P < 0.001). Overall, 62% of patients achieved a complete virological response (CVR) and 37% a partial virological response (PVR). Respective CVR and PVR rates according to subgroup were: HBeAg-positive (21.7% and 78.3%) and HBeAg-negative (84.4% and 15.6%). At 48 weeks, HBV DNA was undetectable in 66.7% of treatment-naïve and 53% of treatment-refractory patients (P = 0.3). Seroconversion occurred in 13 (57%) of HBeAg-positive patients. Two (3%) of the HBeAg-negative patients lost HBsAg at follow up. Mean alanine aminotransferase decreased significantly from 134 U/L before treatment to 37 U/L at 48 weeks (P < 0.001). Significant adverse events were not encountered during the study period.

Conclusion:

Forty-eight weeks of treatment with TDF reduced HBV DNA to undetectable levels in more than half of our patients regardless of whether they were treatment-naïve or refractory. HBeAg-negative (vs positive) patients experienced a better response rate.     

High prevalence of significant histology in asymptomatic chronic hepatitis B patients with genotype C and high serum HBV DNA levels

Summary.  Current treatment guidelines suggest that antiviral therapy be considered for chronic hepatitis B (CHB) patients with high viral load if a biopsy shows significant liver disease despite alanine aminotransferase (ALT) levels two times or less than the upper limit of normal (ULN). We evaluated the histological findings in CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels. Between January 2003 and June 2006, 105 consecutive treatment-naive patients with CHB who underwent ultrasonography-guided percutaneous liver biopsy, had detectable serum HBV DNA (>10⁵ copies/mL) in a direct hybridization assay and normal or slightly elevated serum ALT levels (≤2 × ULN) for at least 12 months were included in a prospective study. Histological assessment was based on the METAVIR scoring system. Significant histology was defined as fibrosis stage ≥F2 or necroinflammation grade ≥A2. Among the 105 CHB patients with high viral load and persistently normal or slightly elevated serum ALT levels for at least 12 months, significant fibrosis (F2–F4 fibrosis) was observed in 63 patients (60.0%) and the actual significant histology was found in 65 patients (61.9%). On multivariate analysis, serum ALT levels and age at which they entered the study were independent factors associated with significant histology. Odds ratios for significant histology increased progressively according to serum ALT levels and age. In conclusion, a large proportion of CHB patients with genotype C, high viral load and ALT ≤2 × ULN had significant liver disease on liver biopsy and should be considered for antiviral therapy.     

Determinants of spontaneous surface antigen loss in hepatitis B e antigen-negative patients with a low viral load

Loss of hepatitis B surface antigen (HBsAg) usually indicates the cure of hepatitis B virus (HBV) infection. In spontaneous hepatitis B e antigen (HBeAg) seroconverters, lower serum HBsAg and HBV DNA levels have been shown to be associated with HBsAg loss over time. However, little is known about their impacts on HBsAg loss in HBeAg-negative patients with limited viral replication. A total of 688 HBeAg-negative patients with baseline serum HBV DNA levels <2000 IU/mL were enrolled in Taiwan. The relationships of HBsAg and HBV DNA levels with subsequent HBsAg loss were investigated. In a mean follow-up of 11.6 years, the average annual rate of HBsAg loss was 1.6%. Baseline HBsAg and HBV DNA levels were inversely associated with subsequent HBsAg loss. When compared to patients who had HBsAg levels >1000 IU/mL, the rates of HBsAg loss were significantly higher in patients with HBsAg levels of 100-999, 10-99, and <10 IU/mL, with hazard ratios of 2.5 (95% confidence interval [CI], 1.6-4.0), 2.8 (95% CI, 1.6-5.0), and 13.2 (95% CI, 8.1-21.5), respectively. Multivariate analysis showed that HBsAg level, but not HBV DNA, remained as an independent factor. The adjusted hazard ratio of HBsAg loss was 13.2 (95% CI, 7.8-22.1) for HBsAg level <10 versus ≥ 1000 IU/mL. When compared to HBV DNA level by receiver operating characteristic curve analysis, HBsAg level served as a better predictor of both 5-year and 10-year HBsAg loss. CONCLUSION: In HBeAg-negative patients with HBV genotype B or C infection who have HBV DNA level <2000 IU/mL, HBsAg level <10 IU/mL is the strongest predictor of HBsAg loss.     

低病毒载量HBeAg阴性慢性HBV感染者肝组织学特点及不同诊断指标对非活动携带的诊断价值

目的探讨低病毒载量HBeAg阴性慢性HBV感染者的肝组织学特点,评价不同临床标准对非活动HBsAg携带(IC)的诊断价值。方法选择HBV DNA4.3lg IU/mL、ALT2×正常值上限(ULN)、HBeAg阴性的慢性HBV感染者为研究对象,观察其肝组织特点,炎症活动指数(HAI)≤3或病变轻微定义为病理学的IC。临床诊断标准:A组为2015年中国指南标准(ALT正常,HBV DNA2.3 lg IU/mL),B组为2015年亚太与美国指南标准(ALT正常,HBV DNA3.3 lg IU/mL),C组为ALT2×ULN、HBV DNA2.3 lg IU/mL,D组为ALT2×ULN,HBV DNA3.3 lg IU/mL)。以肝组织学结果为"金标准"评价四组IC临床诊断标准的价值。结果 171例患者入选,其中男性125例,女46例,年龄22~69岁,平均(45.5±4.2)岁。HAI 1~11分,平均(4.3±2.1)分,其中≤3分者94例,占55.0%;纤维化积分(S)0~4分,平均(2.0±1.6)分,其中0~1分101例,占59.1%。不同临床IC诊断标准筛选的病例与病理IC的符合率没有显著差异。四种筛查方法的约登指数为0.08~0.11,AUC为0.544~0.558,判断IC的价值有限。所有入选病例中符合中国、亚太与欧美指南IC临床诊断的患者,仅有50%~60%符合病理IC,而临床非IC的患者中,有33.3%~51.4%符合病理学的IC诊断。结论低病毒载量HBeAg阴性慢性HBV感染者中有50%~60%的患者符合病理的IC诊断,而临床非IC的患者中,有33.3%~51.4%符合病理学的IC诊断。若以病理结果为IC诊断的"金标准",现有指南推荐的临床标准诊断IC的效率不高,判断价值有限,亚太与美国指南(2015)略有优势。     

替诺福韦治疗慢性乙型肝炎患者疗效及安全性分析*

目的 观察比较应用替诺福韦（TDF）和恩替卡韦（ETV）治疗慢性乙型肝炎（CHB）患者的疗效和安全性。方法 2015年1月~2016年12月我中心收治的初始治疗的CHB患者60例,采用随机数字表法将患者分为两组,每组30例,分别给予TDF或ETV治疗,观察96 w,比较两组血清HBV DNA和丙氨酸氨基转移酶（ALT）水平和阴转率或复常率及不良反应发生情况。结果 在治疗前、治疗第12 w、24 w、48 w、72 w和96 w,TDF治疗组患者血清HBV DNA水平分别为（7.5±0.9）lg IU/mL、（1.7±1.4）lg IU/mL、（1.1±1.0）lg IU/mL、（1.0±0.8）lg IU/mL、（0.7±0.6）lg IU/mL和（0.6±0.5）lg IU/mL,ETV治疗组则分别为（6.8±1.5）lg IU/mL、（2.1±1.1）lg IU/mL、（1.8±1.1）lg IU/mL、（1.0±0.7）lg IU/mL、（0.8±0.8）lg IU/mL和（0.9±0.8）lg IU/mL,在治疗24 w前,TDF治疗组血清HBV DNA水平显著低于ETV治疗组,差异具有统计学意义（P<0.05）; TDF治疗组血清ALT水平分别为（205.8±23.8） U/L、（80.7±8.6） U/L、（49.7±12.5）U/L、（46.2±6.7）U/L、（42.5±6.5）U/L和（41.8±2.4）U/L,ETV治疗组则分别为（199.0±25.9） U/L、（99.8±11.0）U/L、（59.3±9.4）U/L、（53.9±8.8）U/L、（44.62±7.4）U/L和（42.7±4.5）U/L,在治疗24 w前,TDF组血清ALT水平显著低于ETV组（P<0.05）;在治疗第12 w、24 w、48 w、72 w和96 w,TDF组病毒学应答率分别为50.0%、70.0%、73.3%、80.0%和96.7%,而ETV组则分别为23.3%、56.7%、60.0%、70.0%和93.3%,在治疗12 w时,TDF组显著高于ETV组（P<0.05）;TDF组血清ALT复常率分别为63.3%、96.7%、96.7%、100.0%和100.0%,ETV组则分别为50.0%、86.7%、96.7%、96.7%和100.0%,两组无统计学差异（P>0.05）。结论 在当前情况下,应用TDF或ETV任一药物治疗CHB初治患者,均有很好的近期疗效,TDF显示出更早的病毒学应答率,值得进一步观察。     

Plasma HCV-RNA decline in the first 48 h identifies hepatitis C virus mono-infected but not HCV/HIV-coinfected patients with an undetectable HCV viral load at week 4 of peginterferon-alfa-2a/ribavirin therapy

Summary.  During peginterferon-alfa-2a/ribavirin therapy, plasma hepatitis C virus (HCV)-RNA decreases with a rapid first phase and a slower second phase. We compared the viral load decrease and slope in the first 48 h in patients with a rapid viral response (RVR, i.e. HCV-RNA < 50 IU/mL at week 4) with patients not achieving an RVR. From 23 HCV-infected (14 mono-infected and nine HCV/HIV-coinfected) genotype 1 or 4 positive peginterferon-alfa-2a/ribavirin-treated patients, plasma HCV-RNA was determined at baseline, 48 h, weeks 1, 2, 4, 8, 12, 48 and 72. The HCV viral load decrease (Δ0–48), the slope (λ₁) and the efficiency factor (ε) were determined in the first 48 h after the start of therapy. Five (36%) HCV mono-infected patients and three (33%) HIV/HCV-coinfected patients achieved an RVR whereas six (43%) HCV mono-infected patients and five (56%) HIV/HCV-coinfected patients reached a sustained viral response (SVR). In contrast to HIV/HCV-coinfected patients, five HCV mono-infected patients with an RVR showed both a larger Δ0–48 and steeper λ₁ (−1.77log₁₀ IU/mL ± 0.66 and −2.04/day ± 0.76) compared to nine non-RVR patients (−0.66log₁₀ IU/mL ± 0.39; P  = 0.019 and −0.76/day ± 0.41; P  = 0.019). When divided by SVR, a greater Δ0–48 and steeper λ₁ were also seen in both HCV mono-infected and HIV/HCV-coinfected patients. Thus, in the first 48 h after the start of therapy, HCV mono-infected patients with an RVR have a larger viral load decrease, steeper viral slope and a higher efficiency factor as compared with non-RVR patients.     

Prognostic Values of Fluctuations in Serum Levels of Alanine Transaminase in Inactive Carrier State of HBV Infection

Background:

Current guidelines introduce periodic monitoring of serum alanine transaminase (ALT) as the first-line modality in follow-up patients, with a hepatitis B virus (HBV) inactive carrier state.

Objectives:

This study aimed to determine the incidence rate and patterns of ALT fluctuations and prognostic values for the development of chronic HBV e antigen (HBeAg)-negative hepatitis B (CHB), HBV surface antigen (HBsAg) seroclearance, and liver-related complications.

Patients and Methods:

Treatment-naïve patients with a chronic HBV infection, HBeAg(-)/HBeAb(+), normal ALT levels, and HBV DNA < 2000 IU/mL, were followed-up every 6-12 months by assessing serum ALT levels. Serum HBV DNA was measured in cases of elevated ALT levels.

Results:

A total of 399 patients were followed-up for 8.9 years; ALT > upper limit of normal (ULN, i.e. 40 IU/L) was detected in 103 (25.8%) patients, with an annual incidence rate of 2.9%. ALT elevation was associated with; male gender, age, and higher serum ALT levels at study entry. Among the cases of ALT elevations, 16 (15.5%) patients had ALT levels > 2 × ULN. There were 38 (36.9%) patients who had ALT levels that remained > ULN over six months, and 21 (20.4%) patients experienced at least two episodes of ALT elevations. In 15 (14.6%) patients, elevated ALT levels were associated with increased HBV replication (i.e. HBV DNA > 2 000 IU/mL) and these were considered as CHB. However, elevation of ALT levels, even in the absence of HBV replication, increased the risk for the development of CHB up to 8-fold in prospective follow-ups. HBsAg seroclearance, cirrhosis, and hepatocellular carcinoma were detected in 43 (10.8%), 4 (1%), and 1 (0.25%) patients, respectively.

Conclusions:

Fluctuations in serum ALT levels may change the prognosis of a HBV inactive carrier state.     

Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection

OBJECTIVES: In hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection, the clinical relevance of low viremia levels remains unclear. We evaluated the clinical significance of a single baseline serum HBV DNA measurement by a quantitative polymerase chain reaction (PCR) assay in this setting. METHODS: In total, 196 patients with HBeAg-negative chronic HBV infection (62 inactive carriers, 134 with chronic hepatitis B) were studied. ALT activity was normal at baseline in 25/134 HBeAg-negative chronic hepatitis B patients (18.7%), whereas it remained normal throughout follow-up in all inactive carriers. RESULTS: HBV DNA was <30,000 copies/ml in 14 (10.5%) and <100,000 copies/ml in 17 (12.9%) HBeAg-negative chronic hepatitis B patients, whereas it was <30,000 copies/ml in all inactive carriers (undetectable in 14). In particular, HBV DNA levels were <100,000 copies/ml in eight (32%) and <30,000 copies/ml in five (20%) of the 25 patients with HBeAg-negative chronic hepatitis B and normal baseline ALT values. HBV DNA levels with a cut-off at 30,000 or 100,000 copies/ml could correctly classify 92.9% or 91.3% of patients with HBeAg-negative chronic HBV infection, whereas ALT or IgM anti-HBc (IgM class antibody to HBV core antigen) index > 0.200 could correctly classify only 87.2% and 82.1% of patients, respectively. A combined HBV DNA and IgM anti-HBc index performed better by correctly classifying 94.4% of cases. CONCLUSIONS: Serum HBV DNA levels evaluated by sensitive quantitative PCR assays can be used for differentiation between HBeAg-negative chronic hepatitis B and inactive hepatitis B surface antigen carrier state, but the cut-off level should be set at approximately 30,000 copies/ml and certainly lower than the recently suggested level of 100,000 copies/ml.     

Diagnosis and management of pre-core mutant chronic hepatitis B

Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease. Interferon-alpha (IFN-alpha) and lamivudine are the two drugs that have been tried, mainly in the management of HBeAg-negative CHB. A 12-month course of IFN-alpha achieves sustained biochemical remission in about 20% of patients, which has been associated with improvement in the long-term outcome of this subset. A 12-month course of lamivudine is rather ineffective, maintaining remission in less than 15% of patients after cessation of therapy. Long-term lamivudine is associated with progressively increasing rate of virological and subsequent biochemical breakthroughs due to YMDD mutants, with approximately 30% of patients remaining in remission in the third year of therapy. Several other antiviral agents are currently being evaluated in this setting with combined regimens being the most reasonable step for the near future.     

Recurrence of hepatitis B-related hepatocellular carcinoma is associated with high viral load at the time of resection

BACKGROUND/AIMS:  To identify the risk factors for recurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after resection.
METHODS:  Seventy-two patients who underwent liver resection for HBV-related HCC were recruited. Demographic, biochemical, tumor, and viral factors at the time of resection were evaluated by univariate and multivariate analyses to identify risk factors associated with recurrence after resection.
RESULTS:  The median follow-up period was 18.9 months and the median age was 53 yr, with male-to-female ratio of 59:13. Age >60 yr, tumor size >5 cm, poorly differentiated tumor, lymphovascular permeation, the presence of microsatellite lesions, α-fetoprotein (AFP) level >1,000 ng/mL and HBV viral load >2,000 IU/mL (4 log₁₀ copies/mL) at the time of tumor resection, HBV genotype C, core promoter mutations, and patients with no antiviral treatment after tumor resection were associated with increased cumulative risk of HCC recurrence. By multivariate analysis, HBV viral load >2,000 IU/mL (4 log₁₀ copies/mL) ( P = 0.001, odds ratio [OR] 22.3), AFP >1,000 ng/mL ( P = 0.02, OR 7.4), tumor size >5 cm ( P = 0.02, OR 5.1), and age >60 yr ( P = 0.01, OR 4) at the time of tumor resection remained to be the independent risk factors.
CONCLUSIONS:  Viral load of >2,000 IU/mL (4 log₁₀ copies/mL) is the most important correctable risk factor for HCC recurrence after resection. Whether antiviral therapy in these patients can decrease tumor recurrence requires further investigations.