Negative Hepatitis B Virus DNA Research Articles

Lamivudine switch therapy in chronic hepatitis B patients achieving undetectable hepatitis B virus DNA after 3 years of entecavir therapy: A prospective, open-label, multicenter study

The subsequent maintenance therapy in chronic hepatitis B (CHB) patients after long-term viral replication suppression is still uncertain. We aim to evaluate the efficacy of lamivudine (LAM) maintenance therapy in CHB patients achieving undetectable hepatitis B virus (HBV) DNA after 3 years of entecavir (ETV) therapy. Consecutive CHB patients who received at least 3 years of ETV and achieved HBV DNA negativity were allocated either LAM switch therapy or stopped ETV therapy in a prospective, open-label study. Another group of sex- and age-matched patients with continuous ETV therapy for at least 4 years served as historical control group. The primary outcome measurement of the study was relapse of HBV DNA (defined as serum HBV DNA level ≥ 2000 IU/mL). A total of 74 patients, including 42 of LAM switch and 32 of the nonswitch group, were enrolled. There were no significant differences in demographics, except a higher proportion of patients with positive hepatitis B envelope antigen in the nonswitch group at the initiation of ETV therapy. The LAM switch group had significantly lower 1-year relapse rate of HBV within 1 year compared to the nonswitch group (14.3% vs. 75%, p<0.001). However, none of the 48 historical control patients developed relapse of HBV, which was significantly lower than the rate in LAM switch group (p < 0.001). LAM switch was the only factor associated with HBV DNA relapse. In conclusion, continuous long-term potent nucleot(s)ide analogue therapy is mandatory for prevention of viral relapse in CHB patients.

The safety of telbivudine in preventing mother-to-infant transmission of hepatitis B virus in pregnant women after discontinuation

To determine the efficacy and safety of telbivudine for blocking intrauterine transmission of hepatitis B virus (HBV) in pregnant women with high-load HBV DNA. Women in general good health and pragnant were enrolled for study between the ages of 20 to 40 year-old, with a diagnosis of HBV infection with high-load HBV DNA level (≥1*10(6) IU/ml). According to each participant's willingness, the women were divided into a telbivudine treatment group (82 women) and an untreated control group (75 women). The telbivudine treatment was initiated at gestation week 26 as oral dosing of 600 mg/d and continued until 1 month after the birth.Women in the control group had not gotten any antiviral drug treatment. All of the women delivered by cesarean section, and all of the neonates were administered the standard passive immunization therapy, which consisted of a hepatitis B immunoglobulin (200 IU) injection given within 12 hours of birth and an injection of hepatitis B vaccine (20 µg) at birth and at postnatal month 1 and 6. None of the mother's performed breastfeeding. The telbivudine-treated women showed a significant decrease in HBV DNA levels prior to delivery, as well as significantly decreased prenatal HBV DNA levels (>2 logl0). Efficiency of the telbivudine treatment was 100%. Immediately prior to delivery, 16 (19.5%) of the women in the telbivudine treatment group showed negative HBV DNA status, as opposed to the untreated control group in which no women showed negative status. The telbivudine treatment group had no case of maternal or fetal adverse reaction or of congenital malformation. Use of telbivudine antiviral therapy during late pregnancy in women with high-load HBV DNA can significantly reduce level of HBV DNA in maternal peripheral blood, block HBV intrauterine transmission, and provide good short-term efficacy, with good tolerability and safety.

Real life adherence of chronic hepatitis B patients to entecavir treatment

BackgroundReal-life prospective data on adherence to nucleos(t)ide analogues in chronic hepatitis B patients are scarce. AimsWe investigated adherence to entecavir in relation to virological response. MethodsIn this prospective study, we provided 100 consecutive chronic hepatitis B patients with a medication dispenser that monitored entecavir intake during 16 weeks therapy. Hepatitis B virus (HBV) DNA was measured at baseline and after 16 weeks. Beliefs about medicines were evaluated using a questionnaire. ResultsAdherence over 16 weeks averaged 85±17%, with 70% of patients exhibiting good (i.e. ≥80%) adherence. Patients with poor (i.e. <80%) adherence were significantly younger (p=0.01), with more often indifferent attitudes towards entecavir (p=0.03) Viral breakthrough did not occur during the study. Adherence in patients with HBV DNA after 16 weeks >20IU/mL (n=18) and ≤20IU/mL (n=81) averaged 83% and 91% respectively (p=0.19). In multivariate analysis, adherence was not a significant predictor of HBV DNA negativity (adjusted OR 1.02; p=0.34), after adjustment for duration of entecavir treatment (p<0.001) and HBe-status (p=0.001). Conclusions70% of chronic hepatitis B patients exhibited good adherence to entecavir, with younger age and an indifferent attitude being risk factors for poor adherence. Poor adherence was not an independent predictor of virological response.

Hepatitis B virus infection in hemodialysis patients in Japan: Prevalence, incidence and occult hepatitis B virus infection.

A survey of hepatitis B virus (HBV) infection in hemodialysis (HD) patients was conducted to determine the burden and risk of infection and to suggest preventive measures against HBV infection among HD patients at nine hospitals in Hiroshima, Japan, from 1999 to 2003. HBV markers were investigated for 1860 HD patients. The prevalence, incidence of HBV and prevalence of occult HBV were calculated. The prevalence of hepatitis B surface antigen (HBsAg) was 2.6%, the positive rate of anti-hepatitis B core (HBc) was 20.6% and that of anti-hepatitis B surface (HBs) was 11.7%. Among 1372 patients who started HD after the approval of erythropoietin in Japan in 1991, the prevalence of HBsAg was 2.1%. The incidence rate of HBsAg positivity was 0/1000 person-years and the incidence of anti-HBc was 0.3/1000 person-years. Among 1812 HBsAg negative patients HBV DNA was detected in two: one case was negative for anti-HBc and anti-HBs, and the other was only positive for anti-HBc. Prevalence of occult HBV was 0.11%. The incidence rate of HBV was much lower than that of hepatitis C virus (HCV) in the same cohort. We supposed that the discrepancy between incidence rate of HBV and that of HCV was caused by the difference of their carrier rates and of their characteristics for persistent infection. So, we concluded that it is prerequisite to grasp the burden of HBV carriers in the group to prevent new HBV infections in HD patients.

Effects of Hepatitis B Virus Load on Hepatectomy

Background: To investigate the impact of preoperative hepatitis B virus status, as well as postoperative antiviral therapy, on the risk of recurrence-free survival (RFS), overall survival (OS) after curative resection of hepatitis B virus-related hepatocellular carcinoma (HCC) within milan criteria (MC). Patients and methods: A retrospective studies regarding hepatitis B virus-related HCC patients within MC undergoing curative resection from 2007 to 2012 were analysed. Two groups were compared according to preoperative virus status (using 1,000 copies/ml of hepatitis B virus DNA level as cut-off value). Prognostic factors for OS and RFS were evaluated. Additionally, subgroup analysis was conducted in patients with positive hepatitis B virus-DNA (HBV-DNA) to investigate prediction of postoperative antiviral therapy on the long-term prognosis. Results: Patients with positive HBV-DNA had lower OS rates (1 year, 3 year, and 5 year: 91.7%, 77.4%, and 69.6%, respectively) as compared to those with negative HBV-DNA (1-year, 3-year, and 5-year: 95.0%, 82.3%, and 74.6%, respectively) (P=0.041). There were significant differences in RFS rates of the positive vs. negative HBVDNA group (1-year, 3-year, 5-year: 70.8%, 49.3%, 32.8% vs. 73.7%, 53.7%, 41.8%, respectively) (P=0.032). Multivariate analysis revealed that preoperative positive HBV-DNA was an independent risk factor affecting OS (P<0.001) and RFS (P<0.001). The subgroup analysis revealed that postoperative antiviral therapy independently improved OS and RFS (P<0.001). Conclusions: Preoperative positive HBV-DNA of Hepatitis B virus-related HCC patients within MC led to a poor overall and recurrence-free survival than those with negative HBV-DNA after curative resection. To prevent postoperative recurrence, antiviral therapy should be initiated if HBV-DNA ≥ 1,000 copies/ml.

Impact of alpha-fetoprotein on hepatocellular carcinoma development during entecavir treatment of chronic hepatitis B virus infection.

Entecavir (ETV) is one of the first-line nucleoside analogs for treating patients with chronic hepatitis B virus (HBV) infection. However, the hepatocellular carcinoma (HCC) risk for ETV-treated patients remains unclear. A total of 496 Japanese patients with chronic HBV infection undergoing ETV treatment were enrolled in this study. The baseline characteristics were as follows: age 52.6 ± 12.0 years, males 58%, positive for hepatitis B e antigen 45 %, cirrhosis 19%, and median HBV DNA level 6.9 log copies (LC) per milliliter. The mean treatment duration was 49.9 ± 17.5 months. The proportions of HBV DNA negativity (below 2.6 LC/mL) were 68% at 24 weeks and 86% at 1 year, and the rates of alanine aminotransferase (ALT) level normalization were 62 and 72%, respectively. The mean serum alpha-fetoprotein (AFP) levels decreased significantly at 24 weeks after ETV treatment initiation (from 29.0 ± 137.1 to 5.7 ± 27.9 ng/mL, p < 0.001). The cumulative incidence of HCC at 3, 5, and 7 years was 6.0, 9.6, and 17.2%, respectively, among all enrolled patients. In a multivariate analysis, advanced age [55 years or older, hazard ratio (HR) 2.84; p = 0.018], cirrhosis (HR 5.59, p < 0.001), and a higher AFP level (10 ng/mL or greater) at 24 weeks (HR 2.38, p = 0.034) were independent risk factors for HCC incidence. HCC incidence was not affected by HBV DNA negativity or by ALT level normalization at 24 weeks. The AFP level at 24 weeks after ETV treatment initiation can be the on-treatment predictive factor for HCC incidence among patients with chronic HBV infection.

Is hepatitis B immunoglobulin necessary in prophylaxis of hepatitis B recurrence after liver transplantation? A meta-analysis.

Background & AimsApplication of nucleoside analogues and hepatitis B immunoglobulin (HBIG) has reduced hepatitis B virus (HBV) recurrence rate after liver transplantation (LT) dramatically. Recent data suggests therapy without HBIG is also effective. We sought to evaluate the necessity of HBIG in prophylaxis of HBV recurrence after LT.MethodsA meta-analysis was performed. PubMed/MEDLINE, Web of Knowledge and other databases were searched for eligible literatures. The major end points were recurrence rate, patient survival, and YMDD mutant. Risk difference (RD) or risk ratio (RR) was calculated to synthesize the results.ResultsNineteen studies with a total of 1484 patients were included in this analysis. Application of HBIG was helpful to reduce HBV recurrence [P<0.001; RD = 0.16; 95% confidence interval (CI)(0.12, 0.20)] and virus mutants [P<0.001; RR = 3.13; 95%CI (1.86–5.26)], it also improved patients' 1-year [P = 0.03; RD = 0.08; 95%CI (0.01, 0.15)] and 3-year survival rates [P = 0.005; RD = 0.17; 95%CI(0.05, 0.28)]. No significant difference was found for patients' 5-year survival [P = 0.46; RD = −0.06; 95%CI (−0.21, 0.10)]. Sub-group analysis showed that in patients with positive pre-operative HBV DNA status, HBIG was necessary to reduce HBV recurrence rate (P<0.001; RD = 0.42; 95%CI (0.32, 0.52)). In patients with negative HBV DNA, combined therapy gained no significant advantages (P = 0.18; RD = 0.06; 95%CI (−0.03, 0.14)). Non-Lamivudine (non-LAM) antiviral drugs performed as well as combination therapy in prophylaxis of HBV recurrence after LT (P = 0.37; RD = 0.06; 95%CI (−0.02, 0.14)).ConclusionsHBIG with nucleoside analogues is helpful to reduce HBV recurrence and virus mutants. The necessity of HBIG in prophylaxis of HBV recurrence after LT when using new potent nucleoside analogues, especially for patients with negative pre-transplant HBV DNA status remains to be evaluated.

Impact of postoperative hepatitis B virus reactivation in hepatocellular carcinoma patients who formerly had naturally suppressed virus

Hepatitis B virus (HBV) replication detected before the resection of hepatocellular carcinoma (HCC) is to be controlled by antiviral agents. However, management strategy for patients with preoperatively undetectable HBV DNA without antiviral therapy is not clearly delineated. This study investigated viral reactivation after the liver resection in non-replicating HBV DNA-related HCC patients and its impact on the surgical outcome. From 198 patients that underwent liver resection due to HBV-related HCC, 101 patients who had serially checked serum HBV DNA were analyzed. From 101 patients, 33 patients had baseline undetectable HBV DNA. Eleven patients (11/33, 33.3%) had viral replication after the liver resection. The postoperative viral reactivation (HR: 2.144; 95% CI: 1.122-4.097; P = 0.021), along with the existence of satellite nodules (HR: 3.034; 95% CI: 1.1.376-6.689; P = 0.006), existence of microvascular invasion (HR: 2.479; 95% CI: 1.303-4.718; P = 0.006), and HBeAg positivity (HR: 2.059; 95% CI: 1.155-3.670; P = 0.014) predicted recurrence after the surgery. Quantification of intrahepatic total and covalently closed circular DNA (cccDNA) was done in 14 patients whose baseline serum HBV DNA was undetectable without the use of antiviral agent. Amount of intrahepatic cccDNA expressed as copies/hepatocyte in patients with postoperative viral reactivation showed significantly higher than those in patients with sustained negative serum HBV DNA (P = 0.010). This study shows that naturally suppressed preoperative HBV without application of antiviral agent does not ensure undetectable serum HBV after the surgery, and postoperative viral reactivation might be associated with HCC recurrence.

Comparison of telbivudine efficacy in treatment-naive patients with hepatitis B virus-related compensated and decompensated cirrhosis in 96 weeks

Data are limited for comparison of the long-term efficacy of telbivudine (LdT) between hepatitis B virus (HBV)-related compensated and decompensated cirrhosis. The aim of this study was to compare the efficacy of LdT in treatment-naive patients with HBV-related compensated and decompensated cirrhosis in 96 weeks. We reviewed the data of 65 compensated and 62 decompensated cirrhotic patients treated with LdT for 96 weeks, and compared the difference in the related indicators before and after treatment between the groups. Alanine aminotransferase normalized rate was significantly higher in the compensated group than in the decompensated group at weeks 12 and 24 (67.7 vs. 40.3% and 78.5 vs. 53.2%, respectively, P<0.01). Albumin level was much higher than the baseline at week 24 in the compensated group (35.1±6.2 vs. 39.9±5.1, P<0.01), but significance was observed from week 48 onwards in the decompensated group (29.8±3.7 vs. 33.7±3.8, P<0.05). The Child-Turcotte-Puge score either improved or remained steady in both groups. The HBV DNA negativity rate at week 12 (56.9 vs. 32.3%, P<0.01) was higher, whereas the drug resistance rate was lower (P>0.05), in the compensated group than in the decompensated group. The degree of esophageal varix was alleviated, including 11 (16.9%) compensated and four (6.5%) decompensated cirrhotic patients. Liver stiffness was significantly decreased in the compensated group compared with the baseline [19.1 (7.3-32.6) vs. 14.8 (7.4-32.5), P<0.01]; however, there was no statistical significance in the decompensated group compared with the baseline [30.5 (9.1-55.0) vs. 29.9 (8.4-53.2), P>0.05]. Long-term LdT treatment showed superior virological, biochemical, and clinical efficacy in the compensated cirrhotic patients. Therefore, we emphasized the importance of early antiviral treatment, which may improve the prognosis of cirrhotic patients.

Investigation of Hepatitis B and Hepatitis C Virus Infections by Serological and Molecular Methods in Hemodialysis Patients

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are significant causes of morbidity and mortality in hemodialysis patients, since those patients are highly susceptible to infections due to immune suppression. The aims of this study were to investigate the presence of HBV and HCV infections in chronic hemodialysis patients by serological and molecular methods, and to determine the rate of occult HBV infection and the viral genotypes. A total of 201 patients who were under hemodialysis due to end-stage renal disease, were retrospectively evaluated. The study involved the patients at three different centers in Antalya, Turkey during 2006. HBV and HCV markers in the patients' sera were screened by ELISA method, viral nucleic acids were investigated by real-time polymerase chain reaction (PCR) in patients' plasma and viral genotypes were determined by DNA sequence analysis. Detection of at least one of the HBV markers HBsAg, anti-HBc total, and HBV DNA, was accepted as HBV infection, and detection of anti-HCV and/or HCV RNA was accepted as HCV infection. HBsAg positive patients with negative HBV DNA were considered as occult HBV infection. Of the patients 80 (40%) were female, 121 (60%) were male and the mean age was 51.16 ± 16.28 (range 17-93) years. In our study, sole anti-HBs positivity due to HBV vaccination, was detected in 89 (44.3%) patients. One hundred (50%) patients were found positive in terms of HBV infection and 40 (20%) were positive for HCV infection, while 24 (12%) patients had HBV and HCV co-infections. Eighty-five (42.3%) patients had no HBV and HCV infection. Among the 5 (2.5%) patients who were HBsAg positive, four were also HBV DNA positive. Occult HBV infection was detected in 1 (0.5%) patient. Anti-HCV and HCV RNA were found positive in 37 (18.4%) and in 24 (12%) patients, respectively. Among the HCV-RNA positive patients, 3 (12.5%) were anti-HCV negative. ALT and AST levels were found normal in all of the HBV DNA positive patients, and 62.5% (15/24) of HCV RNA positive patients. All of the HBV isolates were identified as genotype D and HCV isolates as genotype 1b. No statistically significant correlation was detected between the HBV infection and patients' age, duration of hemodialysis and elevation of serum transaminase levels (p> 0.05). On the other hand, HCV infection was seen to increase with age (p= 0.047). HCV infection showed a statistically significant increase with the duration of hemodialysis. HCV infection risk was increased in patients who were under hemodialysis for ≥ 25 months (p< 0.001, OR: 0224, 95% CI= 0089-0562). There was also a statistically significant correlation between the presence of HCV infection (anti-HCV and/or HCV RNA positive) and high levels of serum transaminases (p< 0.001). However, in two of the three cases who were anti-HCV negative and HCV RNA positive, serum transaminase levels were normal while the viral loads were high. Therefore to follow-up HCV infection in the hemodialysis patients, anti-HCV and serum transaminase levels may not be sufficient alone and these patients should be evaluated periodically for HCV RNA. In addition, the detection of occult HBV infection in one of the study patients, indicated that HBV DNA should also be investigated at regular intervals in the hemodialysis patients.

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

Inactıve hepatitis B surface antigen carriers and intrafamilial tramsmission: results of a 10-year study.

Background/AimsThe aims of the present study were to determine the outcomes of inactive hepatitis B virus (HBV) surface antigen (HBsAg) carriers over a 10-year study period and to elucidate the HBV serological profile of their family members.MethodsWe retrospectively analyzed the medical files of inactive HBsAg carriers followed up at the Department of Infectious Diseases of Kocatepe University Medical Faculty Hospital between March 2001 and January 2011.ResultsIn total, 438 inactive HBsAg carriers were enrolled in this trial. The follow-up period was 33.7±22.5 months (mean±SD). Anti-hepatitis-B surface antibody seroconversion occurred in 0.7% of cases, while chronic hepatitis B was found in 0.5%. The anti-hepatitis-D virus (HDV) status was evaluated in 400 patients and anti-hepatitis C virus (HCV) in 430. It was found that 1% and 0.2% were positive for anti-HDV and anti-HCV, respectively. HBV serology was investigated in at least 1 family member of 334/438 (76.3%) patients. The HBsAg positivity rate was 34.6% in 625 family members of 334 patients. A comparison of the HBsAg positivity rates in terms of HBV DNA levels in index cases revealed that HBsAg seropositivity rates were higher in family members of HBV DNA-negative patients than in family members of HBV DNA-positive cases (P=0.0001).ConclusionsThe HBsAg positivity rate was higher in family members of inactive HBsAg carriers than in the general population; these family members therefore have a higher risk of HBV transmission. Furthermore, despite negative HBV DNA levels, transmission risk was not reduced in these patients, and horizontal transmission seems to be independent of the HBV DNA value.

Serum HBV RNA as a possible marker of HBV replication in the liver during nucleot(s)ide analogue therapy

We read with interest the article by Tsuge et al. [1] published in the recent issue of the Journal of Gastroenterology. Treatment with nucleot(s)ide analogue (NUC) strongly suppresses the replication of hepatitis B virus (HBV) leading to a high rate of serum HBV DNA negativity. However, the incidence of relapse after the cessation of NUCs is high. Criterion for safe discontinuation of NUC therapy after long term therapy is not established to date. In HBe antigen positive patients, seroconversion, HBV DNA negativity and consolidation therapy of[6 months may be a consensus criteria but 30–50 % of patients fulfilling this criteria experience a relapse. In HBe antigen negative patients, NUC therapy is generally recommended until HBs antigen becomes undetected. Tsuge et al. [1] measured serum HBV RNA plus DNA by real time PCR and showed that the serum HBV DNA ? RNA titer following 3 months of NUC treatment was a significant predictor of early (within 24 weeks) HBV DNA rebound after discontinuation of NUC. The serum HBV DNA ? RNA titer was also associated with ALT rebound in HBe antigen positive patients. The results of the study by Tsuge et al. indicate that serum HBV DNA ? RNA titer may serve as predictor of relapse after discontinuation of NUC. The high rate of relapse after discontinuation of NUC is due to the persistence of HBV replication in the liver even during the NUC therapy. The replicative intermediate form of HBV, covalently closed circular DNA (cccDNA), may not be eliminated by NUC therapy and serves as a template for viral pre-genomic messenger RNA [2]. This concept was proved by a study showing that quantification of intrahepatic HBV cccDNA had a high accuracy of predicting sustained virological response after NUC discontinuation [3]. Still, we need a non-invasive and clinically usable marker for the assessment of HBV replication in the liver during NUC therapy. The measurement of HBV core related antigen may be an alternative [4]. The rationale of measuring HBV RNA in serum was that immature HBV particles including HBV RNA are released from hepatocytes during NUC treatment under the circumstances that pre-genomic HBV RNA are transcribed from HBV cccDNA, packaged into HBV core particles, but not reverse transcribed into plus-strand HBV DNA due to strong interference by NUC, and the excessive amounts of these immature particles are accumulated in hepatocytes [5, 6]. Tsuge et al. showed that serum HBV DNA ? RNA titer following 3 months of NUC treatment was significantly lower in patients with no rebound of HBV DNA. By using a cut-off value of 4.8 log copies/mL, the cumulative incidence of HBV DNA rebound was significantly lower in patients with serum HBV DNA ? RNA titer \ 4.8 log at 3 months of NUC treatment. The same groups previously showed that HBV RNA levels at 3 months of lamivudine treatment were predictor of early emergence of resistant mutations [7]. Taken together, serum HBV DNA ? RNA titer may be linked to the level of HBV replication in the liver during NUC therapy. Monitoring of serum HBV DNA ? RNA response may be utilized in various decision makings in treatment of HBV patients with NUC therapy. Based on these important findings, several questions may remain for future elucidation. Commercially available transcription-mediated amplification and hybridization assay An answer to this letter to the editor is available at doi:10.1007/s00535-013-0801-6.

Efficacy of Lamivudine or Entecavir against Virological Rebound after Achieving HBV DNA Negativity in Chronic Hepatitis B Patients

Nucleos(t)ide analogues (NAs) lead to viral suppression and undetectable hepatitis B virus (HBV) DNA in some individuals infected with HBV, but the rate of virological rebound has been unknown in such patients. We examined the prevalence of virological rebound of HBV DNA among NA-treated patients with undetectable HBV DNA. We retrospectively analyzed 303 consecutive patients [158 entecavir (ETV)- and 145 lamivudine (LAM)-treated] who achieved HBV DNA negativity, defined as HBV DNA < 3.7 log IU/mL for at least 3 months. They were followed up and their features, including their rates of viral breakthrough, were determined. Viral rebound after HBV DNA negativity was not observed in the ETV-group. Viral rebound after HBV DNA negativity occurred in 38.7% of 62 HBe antigen-positive patients in the LAM-group. On multivariate analysis, age was an independent factor for viral breakthrough among these patients (P = 0.035). Viral rebound after HBV DNA negativity occurred in 29.1% of 79 HBe antigen-negative patients in the LAM-group. Differently from LAM, ETV could inhibit HBV replication once HBV DNA negativity was achieved. In contrast, LAM could not inhibit HBV replication even if HBV negativity was achieved in the early phase. Attention should be paid to these features in clinical practice.

Efficacy of combined therapy in patients with hepatitis B virus-related decompensated cirrhosis

To investigate the efficacy and safety of combined de novo lamivudine (LAM) and adefovir dipivoxil (ADV) therapy in hepatitis B virus (HBV)-related decompensated liver cirrhosis patients. One hundred and forty patients with HBV-related decompensated cirrhosis were recruited, 70 patients were treated with combined LAM and ADV de novo therapy, and the other 70 patients were treated with LAM alone as controls. The follow-up period was 144 wk. All patients with LAM resistance were shifted to ADV. The percentage of HBV-related decompensated cirrhosis patients with undetectable HBV DNA in de novo combination group was 51.6% (33/64), 84.2% (48/57), and 92.3% (49/53) by weeks 48, 96, and 144, respectively. In monotherapy group, HBV DNA negativity rate was 46.1% (30/65), 56.1% (32/57), and 39.2% (20/51) by weeks 48, 96 and 144, respectively. There was a significant difference between the two groups by weeks 96 and 144 (P = 0.012 and 0.001). The hepatitis B e antigen seroconversion rate was 28.1% (9/32), 40.0% (12/30), and 53.6% (15/28) in the combination group by weeks 48, 96 and 144, respectively, and 24.2% (8/33), 31.0% (9/29), and 37.0% (10/27) by weeks 48, 96 and 144, respectively, in monotherapy group. A total of 68.6% (44/64), 84.2% (48/57), and 92.5% (49/53) patients achieved alanine aminotransferase (ALT) normalization by weeks 48, 96 and 144, respectively in the combination group. In monotherpy group, the ALT normalization rate was 64.6% (42/65) by week 48, 73.7% (42/57) by week 96, and 80.4% (41/51) by week 144. No patients in the combination group exhibited detectable resistance for at least 144 wk. The cumulative resistance rate in monotherapy group at weeks 48, 96, and 144 was 20.0%, 36.8%, and 56.9%. Both combination group and monotherapy group demonstrated an improvement in Child-Turcotte Pugh and Model for End-Stage Liver Disease scores at weeks 48, 96, and 144. All patients tolerated both combination and monotherapy. The ceratinine levels and glomerular filtration rate remained normal in all patients during the follow-up period. In HBV-related decompensated liver cirrhosis patients, the combined de novo LAM and ADV therapy is more efficacious and safer compared to LAM alone.

Occult Hepatitis B Virus Infection in Patients With Chronic Hepatitis C Treated With Antiviral Therapy

BackgroundOccult hepatitis B virus infection (OBI) is defined as the presence of hepatitis B virus (HBV) DNA in the liver and/or in the serum of patients with negative results of hepatitis B s antigen (HBsAg) test with or without serological markers of previous viral exposure. The impact of OBI in patients with chronic hepatitis C (CHC) is still unclear.ObjectivesThe Aim of this study was to assess OBI prevalence and its potential implications on treatment outcome in a cohort of patients with CHC underwent standard antiviral therapy.Patients and MethodsBaseline serum samples from 137 HBsAg-negative CHC patients treated with pegylated-interferon and ribavirin (73 Responders/74 Non Responders),were retrospectively analyzed for HBV status.ResultsSeventy-three patients (53.3%) showed markers of previous exposure to HBV. HBV DNA was detected in 2 of 137 serum samples (1.5%), both carrying HBV antibodies. Liver biopsies and post-therapy sera were available for 35 patients (12 Responders/23 Non Responders). HBV DNA sequences were found in 13 of 35 specimens (37.1%), all of patients with HBV DNA negativity in basal and post-therapy serum samples. Among OBI-positive patients, 5 (38.5%) carried serological markers of HBV infection. Regarding therapy outcome, in the OBI-positive group there were 5 of 13 (38.5%) sustained virological responders (SVR) compared to 7 of 22 (31.8%) in the OBI-negative one.ConclusionsDespite the high prevalence rate of liver HBV DNA in patients with CHC, SVR was not affected by occult HBV infection.

Prevalence and virological profiles of hepatitis B infection in human immunodeficiency virus patients

To determine the prevalence of hepatitis B virus (HBV) in adult human immunodeficiency virus (HIV) patients with CD4+ T-cell count less than 500/mm(3) and without antiretroviral therapy; to describe different HBV-HIV coinfection virological profiles; and to search for factors associated with HBs antigen (HBsAg) presence in these HIV positive patients. During four months (June through September 2006), 491 patients were received in four HIV positive monitoring clinical centers in Abidjan. HIV-1 or HIV-1 and 2 positive patients, age ≥ 18 years, CD4+ T-cell count < 500/mL and formal and signed consent of the patient. Realized blood tests included HIV serology, CD4+ T-cell count, quantitative HIV RNA load and HBV serological markers, such as HBsAg and HBc antibody (anti-HBcAb). We performed HBeAg, anti-HBe antibody (anti-HBeAb), anti-HBc IgM and quantitative HBV DNA load in HBsAg positive patients. Anti-HBsAb had been tested in HIV patients with HBsAg negative and anti-HBcAb-positive. HBV DNA was also tested in 188 anti-HBcAb positive patients with HBsAg negative status and without anti-HBsAb. Univariate analysis (Pearson χ(2) test or Fischer exact test) and multivariate analysis (backward step-wise selection logistic regression) were performed as statistical analysis. Mean age of 491 patients was 36 ± 8.68 years and 73.3% were female. Type-1 HIV was found in 97% and dual-type HIV (type 1 plus type 2) in 3%. World Health Organization (WHO) clinical stage was 1, 2, 3 and 4 respectively in 61 (12.4%), 233 (47.5%), 172 (35%) and 25 patients (5.1%). Median CD4+ T-cell count was 341/mm(3) (interquartile range: 221-470). One hundred and twelve patients had less than 200 CD4+ T-cell/mm(3). Plasma HIV-1 RNA load was elevated (≥ 5 log(10) copies/mL) in 221 patients (45%). HBsAg and anti-HBcAb prevalence was respectively 13.4% and 72.9%. Of the 66 HBsAg positive patients, 22 were inactive HBV carriers (33.3%), 21 had HBeAg positive hepatitis (31.8%) and 20 had HBeAg negative hepatitis (30.3%). HBeAg and anti-HBeAb were indeterminate in 3 of them. Occult B infection prevalence (HBsAg negative, anti-HBcAb positive, anti-HBsAb negative and detectable HBV DNA) was 21.3%. Three parameters were significantly associated with the presence of HBsAg: male [odds ratio (OR): 2.2; P = 0.005; 95% confidence interval (CI): 1.3-3.8]; WHO stage 4 (OR: 3.2; P = 0.01; 95% CI: 1.3-7.9); and aspartate aminotransferase (AST) level higher than the standard (OR: 1.9; P = 0.04; 95% CI: 1.02-3.8). HBV infection prevalence is high in HIV-positive patients. HBeAg positive chronic hepatitis and occult HBV infection are more frequent in HIV-positive patients than in HIV negative ones. Parameters associated with HBsAg positivity were male gender, AIDS status and increased AST level.

Entecavir Therapy for Patients with Hepatitis B Virus-related Decompensated Cirrhosis

Entecavie (ETV) has a potent antiviral effect and low rates of resistance in hepatitis B virus (HBV) and is the first-line monotherapy in patients with HBV-related decompensated cirrhosis. We evaluated the efficacy of 12 months treatment with ETV and tried to determine predictive factors of response. Forty-five consecutive decompensated cirrhotic patients who received ETV (0.5 mg/day) for more than six months were included. All patients were positive for HBV DNA, and the Child-Turcotte-Pugh (CTP) scores were over 8 point. Seventeen patients were HBeAg-positive. CTP score, model for end-stage liver disease (MELD) score, serum markers of liver function and HBV DNA were assessed every 3 months. ETV treatment for 12 months resulted in improvement of CTP and MELD scores. Pre-treatment mean CTP and MELD score were decreased from 10.1 (±2.0) and 13.48 (±4.05) to 7.24 (±2.0) and 9.68 (±4.85) at 12 months, respectively. The 1-year cumulative rates of HBV DNA negativity and HBeAg loss were 88.9% and 52.9%, respectively, by intention-to-treat analysis. Thirty-two (71.1%) showed improvement in CTP score. Eleven patients did not show change, and 2 patients got worse. The AST/ALT, albumin, bilrubin, prothrombin time were significantly normalized within six months. The good responder group had high level of prothrombin time than the poor responder group (p=0.004). Our result shows that entecavir can improve liver function in about 70% of patients with HBV related decompensated liver cirrhosis. INR may be a predictive factor of good response with entecavir in these patients.

Intrahepatic response markers in chronic hepatitis B patients treated with peginterferon alpha‐2a and adefovir

We investigated whether intrahepatic markers could predict response in chronic hepatitis B virus (HBV) patients treated with peg-interferon and adefovir for 48 weeks. Intrahepatic covalently closed circular DNA (cccDNA), total intrahepatic HBV DNA and the proportion of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) positive hepatocytes in 16 hepatitis B e antigen (HBeAg) positive and 24 HBeAg negative patients were measured at baseline and at end of treatment. Baseline intrahepatic markers were not associated with sustained virological response (SVR) defined as HBV DNA < 2000 IU/mL and persistent normal alanine aminotransferase levels at the end of follow-up (week 72). At end of treatment, intrahepatic cccDNA and total intrahepatic HBV DNA in HBeAg positive patients were significantly lower in patients with HBeAg seroconversion (P = 0.016 and P = 0.010) with positive predictive values (PPV) for SVR of 80% and 80%, respectively. In HBeAg negative patients, intrahepatic cccDNA and total intrahepatic HBV DNA had declined significantly at end of treatment (P = 0.035 and P = 0.041) and corresponding PPV for SVR was 73% and 82%. In HBeAg positive patients, median proportion of HBcAg positive hepatocytes declined significantly (P = 0.002) at end of treatment. In HBeAg negative patients, the proportion of HBsAg positive hepatocytes had declined significantly at end of treatment (P = 0.0009). Using HBsAg ≤ 7.5% as a limit, PPV for SVR in HBeAg negative patients was 83%. At end of treatment in HBeAg positive patients, intrahepatic cccDNA and total intrahepatic HBV DNA were predictive for SVR. In HBeAg negative patients a proportion of < 7.5% HBsAg positive hepatocytes at end of treatment was a strong predictor for SVR.

Emergence of entecavir-resistant mutations in nucleos(t)ide-naive Japanese patients infected with hepatitis B virus: Virological breakthrough is also dependent on adherence to medication

Objective. Currently, five nucleos(t)ide analogues (NUCs) are available for the treatment of chronic hepatitis B in the world. We examined the prevalence of hepatitis B virus (HBV) DNA and alanine aminotransferase normalization in patients receiving entecavir (ETV) and the frequency of ETV-resistant mutations during an approximately 27-month use of ETV in chronic hepatitis B patients in an urban hospital in Japan. Materials and methods. A retrospective analysis of 81 NUC-naive chronic hepatitis B patients who received 0.5 mg of ETV daily was performed. HBV DNA was measured and sequence analysis of HBV DNA was performed in virological breakthrough patients. Results. Hepatitis B e antigen (HBeAg)-positive patients with HBV DNA 5.0–7.0 log IU/mL group and all HBeAg-negative patients achieved serum HBV DNA negativity by 12 months. Four patients experienced virological breakthrough during ETV therapy. Two patients had no genotypic mutations, and medical interviews revealed that they had poor adherence to ETV. Conclusions. We found that some of the HBV virological breakthroughs during ETV treatment were related to poor adherence to medication, highlighting that clinicians should pay attention to the emergence of resistant mutants as well as adherence to ETV.