Baseline HBV DNA Research Articles

IL28B polymorphisms predict interferon-related hepatitis B surface antigen seroclearance in genotype D hepatitis B e antigen–negative patients with chronic hepatitis B

Interleukin (IL)28B polymorphisms have been associated with interferon (IFN)-induced viral clearance in patients with chronic hepatitis C. Whether this is also true for patients with the difficult-to-cure hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) is unknown. One hundred and one HBeAg-negative patients (92% genotype D) with compensated CHB (84% males, 46 years; hepatitis B virus [HBV] DNA: 6.0 log cp/mL; alanine aminotransferase [ALT]: 136 IU/L; 42% with cirrhosis) were followed up for a median of 11 years (range, 1-17) after a median of 23 months (range, 10-48) of either standard or pegylated (Peg)-IFN-alpha therapy. A post-treatment response was defined as hepatitis B surface antigen (HBsAg) clearance with or without antibody to hepatitis B surface antigen (anti-HBs) seroconversion. The rs12979860 (C>T) genotype in the IL28B locus was assessed in serum samples by using Custom TaqMan SNP Genotyping Assays (Applied Biosystems, Carlsbad, CA). During a median of 11 years of post-treatment follow-up, 21 patients (21%) cleared serum HBsAg, including 15 who developed>10 IU/mL of anti-HBs titers. Forty-eight patients (47%) had CC genotype, 42 (42%) had CT, and 11 (11%) had TT, with the allelic frequency being 68% for C allele and 32% for T allele. The rate of serum HBsAg clearance was 29% (n=14) in CC compared to 13% (n=7) in non-CC, genotype carriers (P=0.039). Baseline HBV DNA levels<6 log cp/mL (odds ratio [OR], 11.9; 95% confidence interval [CI]: 2.8-50.6; P=0.001), ALT levels>136 IU/L (OR, 6.5; 95% CI: 1.8-22.5; P=0.003), duration of IFN (OR, 1.16; 95% CI: 1.02-1.31; P=0.021), and genotype CC (OR, 3.9; 95% CI: 1.1-13.2; P=0.025) independently predicted HBsAg clearance. IL28B polymorphism is an additional predictor of off-therapy IFN-related HBsAg seroclearance to be used in the pretreatment stratification of HBeAg-negative patients chronically infected by genotype D of HBV.

Viral load and alanine aminotransferase correlate with serologic response in chronic hepatitis B patients treated with entecavir

Although entecavir has been shown to have good efficacy and low resistance for the treatment of chronic hepatitis B (CHB), factors associated with a favorable response remain unknown. This was a retrospective, multicenter study of 248 treatment-naïve hepatitis B e antigen (HBeAg)-positive patients (69.4% male; median age, 39.4 years) treated with entecavir for more than 1 year, and 15.7% of them had cirrhosis at baseline. The primary endpoints were HBeAg loss and/or seroconversion. The median baseline levels of alanine aminotransferase (ALT) and hepatitis B virus (HBV) DNA were 201 U/L (range, 27-2415 U/L) and 7.6 log(10) IU/mL (range, 2.2-13.18), respectively. The median treatment period was 25.3 months (range, 12-69.6). The rates of ALT normalization at years 1, 2, and 3 were 83.1%, 87.9%, and 94.9%, respectively. The cumulative rates of HBeAg loss at years 1, 2, and 3 were 20.3%, 38.0%, and 48.9%, respectively. The rates of undetectable HBV-DNA at years 1, 2, and 3 were 52.1%, 78.9%, and 82.5%, respectively. Using Cox proportional hazards model, multivariate analysis showed that baseline ALT greater than five times the upper limit of normal, and viral load were independent factors associated with HBeAg loss (hazard ratio: 1.81, and 0.812; 95% confidence interval: 1.062-3.085; 0.7-0.942, respectively). Entecavir treatment for 3 years can achieve good biochemical and virologic responses in HBeAg-positive CHB patients, but has a modest effect on HBeAg loss and/or seroconversion. In addition, baseline serum ALT and HBV-DNA levels are independent factors associated with favorable treatment responses.

Early Viral Suppression Predicts Good Postoperative Survivals in Patients with Hepatocellular Carcinoma with a High Baseline HBV-DNA Load

To correlate early HBV-DNA suppression by antiviral treatment with posthepatectomy long-term survivals in patients with HBV-related hepatocellular carcinoma (HCC). A retrospective study was conducted on patients with a baseline HBV-DNA load of >2,000 IU/ml. The cumulative rates of HBV-DNA undetectability at weeks 24 and 48, as well as long-term tumor recurrence and overall survivals were determined. Of 1,040 patients with a high baseline HBV-DNA load, 865 patients received antiviral treatment. At a median follow-up of 42 months, 616 patients (59.2 %) had developed HCC recurrence and 482 patients (46.3 %) had died. The median time to recurrence was 25 months. In patients who received antiviral treatment, the cumulative rates of HBV-DNA undetectability (<200 IU/ml) were 54.3 and 88.1 % at weeks 24 and 48, respectively. There was no significant difference between the two groups of patients who received antiviral treatment or not for disease-free survival. On multivariate analyses, tumor size >5 cm, blood transfusion, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak inflammation score were significant risk factors of HCC recurrence. Also, tumor size >5 cm, surgical margin <1 cm, presence of satellite nodules, presence of portal vein tumor thrombus and high Ishak fibrosis score were significant factors associated with poor postoperative overall survival. On the other hand, an undetectable HBV-DNA level before week 24 was a significant protective factor of disease-free survival and overall survival. Early HBV-DNA suppression with antiviral treatment improved prognosis of patients with HBV-related HCC.

Efficacy of telbivudine in Taiwanese chronic hepatitis B patients compared with GLOBE extension study and predicting treatment outcome by HBV DNA kinetics at Week 24

BackgroundThe aims of this study were to compare results from a Taiwanese sub-study of the GLOBE 2303 telbivudine study and evaluate the HBV DNA kinetics.MethodsForty-one Taiwanese patients were treated for an additional 2 years with telbivudine. Efficacy endpoints were the same as the GLOBE study. The correlations of reductions in HBV DNA levels at Week 24 were evaluated.ResultsAll 7 HBeAg-positive patients with undetectable HBV DNA levels at Week 24 sustained this response at Year 4 with rates of ALT normalization 71%, HBeAg seroconversion 57%, and cumulative resistance 0%. Out of 16 HBeAg-negative patients with undetectable HBV DNA levels at Week 24, 11 (78%) sustained this response at Year 4 with rates of ALT normalization 83% and cumulative resistance 8.7%. There were significant correlations between reductions of DNA of ≥5 log10 copies/mL at Week 24 with maintained PCR negativity at Years 2–4 and a lack of resistance at Year 2.ConclusionsLong-term telbivudine efficacy in Taiwanese patients was comparable to the GLOBE 2303 study. A reduction in HBV DNA levels by ≥5 log10 copies/mL at Week 24 represented the optimal cut-off point, which may predict favourable outcomes in patients with high baseline HBV DNA levels.Trial registrationClinicalTrials.gov Identifier: NCT00142298 (http://clinicaltrials.gov/).

A 96-Week Randomized Trial of Switching to Entecavir in Chronic Hepatitis B Patients with a Partial Virological Response to Lamivudine

Growing numbers of chronic hepatitis B (CHB) patients in the Asia-Pacific region have failed first-line therapy with low genetic barrier drugs. This prospective, 96-week study investigated the antiviral efficacy, safety and tolerability of switching to entecavir versus maintaining lamivudine in CHB patients with a partial virological response to lamivudine. A total of 72 hepatitis B e antigen (HBeAg)-positive patients, with serum HBV DNA≥60 IU/ml after ≥6 months lamivudine monotherapy were randomized 1:1 to receive either entecavir 1.0 mg/day, or continued lamivudine 100 mg/day. Mean duration of prior lamivudine treatment was 15.1 months in the lamivudine-maintained patients and 16.1 months in the entecavir-switch patients, with mean baseline HBV DNA levels of 4.66 and 4.55 log(10) IU/ml, respectively. A greater proportion of entecavir-switch than lamivudine-maintained patients achieved undetectable HBV DNA at all time points (67.6% versus 11.4% at week 96; P<0.001). Entecavir-switch patients achieved a greater mean decrease in HBV DNA level by week 4, maintained through week 96. Entecavir-switch patients with baseline HBV DNA<5 log(10) IU/ml were more likely to achieve a virological response at week 96. A total of 6 (17.6%) entecavir-switch and 2 (5.7%) lamivudine-maintained patients achieved HBeAg loss, and 3 (8.8%) entecavir and 1 (2.9%) lamivudine patients achieved HBeAg seroconversion. Genotypic resistance to the assigned intervention emerged in 82.9% (29/35) of lamivudine-maintained patients, and in 3% (1/34) of entecavir-switch patients after 96 weeks. Switching to entecavir in patients with a partial virological response to lamivudine resulted in increased virological efficacy and lower rates of antiviral resistance than maintaining lamivudine.

Lamivudine prophylaxis for hepatitis B virus carrier patients with breast cancer during adjuvant chemotherapy

This study aimed to assess the efficacy of lamivudine prophylaxis on hepatic complications in HBsAg-positive patients with breast cancer undergoing adjuvant chemotherapy and to describe the temporal trend in HBV surveillance and prophylaxis during the last decade. Patients with stage I-III curatively resected invasive breast cancer who received adjuvant and/or neoadjuvant chemotherapy between 2000 and 2009 were eligible for this study. Patients with positive HBsAg and normal liver function were enrolled. Hepatotoxicity, defined as alanine aminotransferase (ALT) ≥100 IU/ml, and HBV reactivation were compared according to lamivudine prophylaxis. Annual trends in HBV surveillance and use of lamivudine prophylaxis were also reviewed. One hundred sixty-five HBsAg-positive patients with breast cancer were enrolled. After the year 2004, surveillance of HBV infection status and use of lamivudine prophylaxis increased significantly (2.5 vs. 57.6 %, P < 0.001). Seventy-three (44.2 %) patients received lamivudine prophylaxis and 92 (55.8 %) patients did not. The incidence of hepatotoxicity was significantly lower in the group receiving prophylaxis (2.7 vs. 14.1 %, P = 0.011) with fewer premature terminations of planned adjuvant chemotherapy (0 vs. 10.9 %, P = 0.004) in the prophylaxis group. Among the patients for whom the baseline HBV DNA titer was available, the HBV reactivation rate was lower, albeit not significantly, in the prophylaxis group (0 %) compared with the no prophylaxis group (20 %) (P = 0.104). Lamivudine-withdrawal hepatitis was not detected; however, one case of breakthrough HBV reactivation during lamivudine treatment was observed in this study. Over the past decade, there has been an increase in the awareness of HBV reactivation and in the use of lamivudine during cytotoxic chemotherapy. Lamivudine prophylaxis reduced hepatic complications during adjuvant chemotherapy in patients with breast cancer. Lamivudine prophylaxis should be considered in HBsAg-positive patients with breast cancer who are candidates for adjuvant chemotherapy.

Pre-S Mutation Is a Significant Risk Factor for Hepatocellular Carcinoma Development: A Long-Term Retrospective Cohort Study

Several cross-sectional studies have shown an association between pre-S mutation and hepatocellular carcinoma (HCC). We aim to verify whether pre-S mutation represents a risk for HCC development in a longitudinal way. A total of 195 patients with chronic HBV infection [age: 43.7±10.8years, males: 141 (72.3%), genotype C: 195 (100%), hepatitis B e antigen (HBeAg) positive: 109 (55.9%), cirrhosis: 79 (40.5%), and pre-S mutation positive: 44 (22.6%)] were followed up for a median of 7.2years (range 1.0-7.8years). HCC developed in 24 patients during follow-up. The 1-, 3-, and 5-year cumulative incidences of HCC were 0.5, 4.9, and 10.4%, respectively. Patients with pre-S mutation had significantly higher 5-year cumulative incidences of HCC than those without (26.5 vs. 5.7%, p<0.001) and showed higher hazard ratio for HCC [3.04 (95% CI 1.24-7.42), p=0.015, adjusted for age, gender, HBeAg, cirrhosis and baseline HBV DNA level]. Notably, in patients aged ≥50years, the 5-year cumulative incidences of HCC in patients with pre-S mutation were considerably high (58.3%), compared to those without (16.1%, p<0.001). Patients with pre-S mutations had higher incidence of HCC during follow-up, especially in aged patients. Patients with pre-S mutations, especially older ones, may require careful attention to HCC development.

Emergence of lamivudine resistance hepatitis B virus mutations in pregnant women infected with HBV and HIV receiving antiretroviral prophylaxis for the prevention of mother‐to‐infant transmission in Malawi

HIV/HBV co-infection is highly prevalent in sub-Saharan Africa. The aim of this study was to determine if the use of triple combination lamivudine-containing prophylaxis for the prevention of mother-to-infant HIV transmission was associated with the emergence of lamivudine HBV mutations. The study included 21 pregnant co-infected women in Malawi who received either zidovudine or stavudine plus lamivudine and nevirapine from week 25 of gestation until 6 months after delivery or indefinitely if they met the criteria for treatment (CD4+ <350/mm(3)). HBV-DNA was determined using the Roche COBAS assay. Resistance mutations were assessed by the Trugene assay (Siemens Diagnostics). At baseline 33% of the women were HBeAg positive and had HBV-DNA > 10(4) IU/ml. Median CD4 count was 237 cells/mm(3) and median HIV-RNA was 3.8 log(10) copies/ml. After a median of 259 days of treatment, HBV-DNA was detectable in 9 out of 21 patients (42.8%). In three cases the HBV-DNA level was >10(4) IU/ml. Resistance mutations (M204I in five cases and L180M + M204I/V in one case) were present in 6 (28.6%) patients. Women with a resistant virus had significantly higher baseline HBV-DNA levels than those not developing resistance (1.1 × 10(7) IU/ml vs. 20.8 IU/ml, P = 0.022). Levels of ALT and AST were higher in women with resistant viruses compared to those retaining a wild-type virus. A high rate of lamivudine resistance was seen in this cohort of pregnant women. Follow-up of these patients will clarify if the presence of resistance has a significant impact on liver disease.

6.0 HIV and hepatitis virus coinfections

6.0 <scp>HIV</scp> and hepatitis virus coinfections

Relationship between serum hepatitis B virus DNA load and hepatocellular carcinoma in Qidong, China: a cohort follow-up study of 14 years

To explore the relationship between serum HBV DNA load and hepatocellular carcinogenesis in Qidong HBsAg carriers. In 1997, 477 HBsAg carriers and 477 age, gender and residence matched HBsAg negative controls were enrolled as a prospective cohort in Qidong city. The entry serum samples were detected for the levels of HBeAg and HBV DNA. The relationship between baseline HBV DNA load and hepatocellular carcinoma (HCC) during the follow-up period from June 1997 to June 2011 were analyzed. The total observed person-years (PY) were 12 200. Eighty-seven patients developed HCC with an incidence of 1498/100 000 PY in the HBsAg positive group versus 6 with an incidence of 94/100 000 PY (P = 0.000) in the HBsAg negative group. The relative risk (RR) was 15.96. N o significant difference existed between the incidences of other tumors in two groups (P = 0.161). Compared with the HBsAg negative group, the RR of HCC was 11.38 (95%CI 4.87 - 26.62, P < 0.01)in the HBsAg+/HBeAg- group and 29.08 (95%CI 12.37 - 68.37, P < 0.01) in the HBsAg+/HBeAg+ group; 5.80 (95%CI 2.29 - 14.70, P < 0.01) in the HBsAg+/HBV DNA- group and 27.75 (95%CI 12.07 - 63.81, P < 0.01) in the HBsAg+/HBV DNA+ group. In HBsAg positive subjects, while the HBV DNA load was classified into 5 levels namely 250 - 10(4), 10(4)-, 10(5)-, 10(6)- and ≥ 10(7) copies/ml, the relative risks for HCC at each level were 2.84 (95%CI 1.44 - 5.61, P < 0.01), 5.75 (95%CI 2.77 - 11.95, P < 0.01), 9.05 (95%CI 4.71 - 17.41, P < 0.01), 6.39 (95%CI 2.79 - 14.64, P < 0.01) and 4.35 (95%CI 2.21 - 8.56, P < 0.01) respectively versus the < 250 copies/ml group. HBV DNA is an important risk predictor of hepatocellular carcinoma. The HBsAg carriers with the serum loads of HBV DNA between 10(5) - 10(6) copies/ml are most likely to present with HCC.

520 RESPONSE TO TENOFOVIR TREATMENT OF TREATMENT-NAIVE VS ADEFOVIR-RESISTANT VS SUBOPTIMAL RESPONDER PATIENTS WITH CHRONIC HEPATITIS B

Tenofovir (TVF) is known to possess potent and similar antiviral efficacy against treatment-naive and lamivudine-resistant chronic hepatitis B (CHB). TVF may be less effective against adefovir (ADV)resistant CHB (van Bommel et al, Hepatology 2010). These data need confirmation. Aim:We aimed to assess antiviral efficacy of TVF against treatmentnaive (TN) and ADV-resistant (ADV-R) CHB and suboptimal ADV (ADV-S) responders. Methods: The database of 2 tertiary referral centers was analyzed. HBV DNA had been measured with Cobas Taqman (Roche Diagnostics; detection limit 20 IU/mL) at 3-monthly intervals in the first year and then every 6 months. Data of 24 months of treatment were analyzed in a total of 135 patients (52 TN, 55 ADV-R, 28 AD-S). HBV DNA measurements were available at months 3, 6, 9, 12, 18 and 24 in 49, 43, 39, 40, 32 and 23 TN; 37, 49, 38, 41, 33 and 23 ADV-R and 26, 28, 26, 25, 24 and 21 ADV-S patients, respectively. Results: The 3 groups were similar with regard to age, sex and HBeAg-status. T-N patients had higher baseline HBV DNA compared to ADV-R and ADV-S groups (6.7 log10 IU/mL vs. 5.9 and 5.6, p = 0.004, respectively). Cirrhosis was present in 11, 21 and 29% of TN, ADV-R and ADV-S patients (p = 0.033). By exponential regression analysis, no difference between HBV DNA decline kinetics between the 3 groups was observed. However, by linear regression analysis of the first 3 months data HBV DNA decline was faster in TN patients compared to ADV-R CHB. Undetectable HBV DNA was achieved in 63%, 60% and 76% of TN, ADV-R and ADV-S CHB patients at week 48 (p =NS). Corresponding figures were 70%, 80% and 86% (p =NS). Conclusion: Over a 24 month period, HBV DNA decline kinetics were similar in TN CHB and patients with ADV-R and ADV-S CHB. Only in the first 3 months, HBV DNA decline was slower in ADV-R patients suggesting that in AD-R patients with critical liver reserve combination treatment could be considered (Peterson et al, J Hepatol 2011-in press).

Lamivudine plus adefovir vs. entecavir in HBeAg‐positive hepatitis B with sequential treatment failure of lamivudine and adefovir

Few studies have adequately examined the efficacy of lamivudine plus adefovir (LAM+ADV) combination therapy vs. entecavir (ETV) monotherapy in HBeAg-positive hepatitis B patients who fail to respond to sequential treatment with LAM and ADV. We compared directly the efficacy of LAM+ADV vs. ETV in such patients and assessed prognostic factors associated with a virologic response at month 12. In total, 72 HBeAg-positive patients who showed resistance (n = 33) or a suboptimal virologic response (n = 39) to ADV monotherapy with resistance to LAM therapy underwent rescue therapy (31 LAM+ADV and 41 ETV). All patients were followed for at least 12 months. Following 12 months of treatment, in the LAM+ADV and ETV groups, a virologic response was observed in 7/31 (22.6%) and 8/41 (19.5%; P = 0.777) patients; ALT normalization occurred in 11/13 (84.6%) and 16/18 (88.9%; P = 0.566); HBeAg seroconversion in 1/31 (2.3%) and 4/41 (9.8%; P = 0.341) and a virologic breakthrough in 3/31 (9.0%) and 5/41 (12.1%; P = 0.452) respectively. Independent prognostic factors associated with a virologic response were the baseline HBV-DNA level (OR = 0.37; 95% CI 0.17-0.80; P = 0.011) and the duration of prior ADV monotherapy (OR = 0.89; 95% CI 0.83-0.95; P = 0.044). Neither LAM+ADV nor ETV was adequately effective in patients with sequential LAM and ADV treatment failure. Thus, when chronic hepatitis B patients show resistance or suboptimal response to ADV monotherapy, early modification of treatment should be considered.

Five‐year on‐treatment efficacy of lamivudine‐, tenofovir‐ and tenofovir + emtricitabine‐based HAART in HBV–HIV‐coinfected patients

Data on the efficacy of lamivudine (LAM)-, tenofovir (TDF)- and emtricitabine (FTC)-based antiretroviral therapy (HAART) in HBV-HIV coinfection are limited. We completed a retrospective analysis of HBV-HIV-coinfected patients treated at the Medical University of Vienna. One-hundred and ten coinfected patients were included, with 57% being initially HBV e-Antigen (HBeAg) positive. Baseline HBV load was significantly higher in HBeAg+ than in HBeAg- patients (5962 ± 3663 vs 20 ± 19 × 10(6) IU/mL; P < 0.0001). Over a median observation period of 83 month (range: 26-183), 87% received HAART and 91% showed a suppression of HBV replication. After 5 years of continuous treatment, HBeAg seroconversion was achieved in 21% of LAM-, 50% of TDF- (P = 0.042 vs LAM) and in 57% of TDF + FTC (P = 0.008 vs LAM)-treated patients, respectively. HBsAg loss after 5 years was found in 8% (LAM), 25% (TDF; P = 0.085 vs LAM) and 29% (TDF + FTC; P = 0.037 vs LAM) of HBeAg+ patients. In HBeAg- patients, HBsAg loss was achieved in 11% (LAM), 27% (TDF; P = 0.263 vs LAM) and 36% (TDF + FTC; P = 0.05 vs LAM), respectively. Pretreatment CD4+ counts did not influence rates of HBeAg seroconversion and of HBsAg loss. Patients with HBsAg loss had lower baseline HBV-DNA levels and higher AST/ALT levels than patients without HBsAg loss. Transient HAART-related hepatotoxicity was found in 32% (Grade I: 21%; II:7%; III:2%; IV:0%). Most HBV-HIV-coinfected patients achieve complete suppression of HBV replication despite high baseline viremia. TDF-based HAART leads to high rates of HBeAg seroconversion and HBsAg loss after 5 years of continuous exposure. One-third of HBV-HIV-coinfected patients may experience transient HAART-related hepatotoxicity.

Assessment of HBV flare in a randomized clinical trial in HIV/HBV coinfected subjects initiating HBV-active antiretroviral therapy in Thailand

BackgroundHepatic Flare (HF) after initiation of highly active antiretroviral therapy (HAART) in HIV-HBV coinfected individuals is well recognized but prospective data on predictors and subsequent outcome are limited.MethodsThe Tenofovir in HIV-HBV coinfection study was a randomized clinical trial of HBV-active HAART including lamivudine and/or tenofovir in antiretroviral naïve HIV-HBV individuals in Thailand.ResultsEarly HF (EHF) was defined as ALT > 5 × ULN during the first 12 weeks. EHF was observed in 8 (22%) of individuals at a median of 56 days. 6/8 EHF cases were asymptomatic and resolved with HAART continuation, however one subject with underlying cirrhosis died following rapid hepatic decompensation. EHF was significantly associated with higher baseline ALT (79 IU/L vs 36 IU/L non-EHF, p = 0.008) and HBV DNA (9.9 log10 c/ml vs 8.4 log10 c/ml non EHF, p = 0.009), and subsequent serological change. HBeAg loss occurred in 75% of EHF cases versus 22% in non-EHF (p = 0.04), and HBsAg loss in 25% of EHF cases versus 4% of non-EHF (p = 0.053).ConclusionEHF after HBV active HAART initiation was frequently observed in this population. Timing of EHF, association with elevated ALT and HBV DNA and high rate of seroconversion are all consistent with immune restoration as the likely underlying process.Clinical Trial numberNCT00192595.

Effect and Predictive Elements for 52 Weeks’ Telbivudine Treatment on Naïve HBeAg Positive Chronic Hepatitis B

: Background: Antiviral treatment with nucleoside analogs has been used for chronic hepatitis B (CHB). each kind of nucleoside analog has its own characteristics and suitability for patients. Telbivudine (LdT, brand name: Sebivo, Beijing novartis pharma Ltd) is the newest nucleoside analog, with strong and rapid viral suppression. However, its resistance rate is relatively high during long-term application, due to low genetic barriers to resistance. So, it is necessary to increase the effect and reduce resistance with effective management, according to baseline factors and early on-treatment responses. Objectives: To reveal possible predictive factors of the effect of telbivudine (LdT) treatment on naïve HBeAg-positive chronic hepatitis B (CHB) patients to optimize treatment. Patients and Methods: A total 71 naïve chronic hepatitis B (CHB) patients who met the inclusion criteria were enrolled. All patients were treated with LdT 600 mg Qd for at least 52 weeks. Multiple logistic regression analyses were done to investigate the predictive values of baseline factors and responses at Week 24. Results: The reduction in hepatitis virus B (HBV) DnA level was 6.44 ± 2.38 lg copies/mL at Week 52 compared with baseline. The complete virus response (CVR), biochemical response (BR), serological response (SR), and drug resistance (DR) were 61.99%, 77.46%, 35.21%, and 8.45% respectively. By multiple regression analysis, baseline alanine aminotransferase (ALT) levels significantly affected CVR (P = 0.024, oR = 1.008), and baseline ALT and baseline HBV DnA levels were independent compact factors of SR (P = 0.012, oR = 1.007; P = 0.001, oR = 0.423). The differences in CVR, SR, and DR in patients with ALT > 120 Iu/mL compared with patients with ALT ≤ 120 Iu/mL were statistically significant. The differences in SR in patients with HBV DnA > 107 copies/mL compared with patients with HBV DnA ≤ 107 copies/mL were statistically significant. Additionally, CVR, BR, and SR were differed significantly between patients with HBV DnA lower than 300 copies/mL at Week 24 and patients with HBV DnA higher than 300 copies/mL (P = 0.000, P = 0.0016, and P = 0.000, respectively). Conclusions: There were more responders among naïve HBeAg-positive chronic hepatitis B patients with lower HBV DnA levels (especially lower than 107 copies/mL) and higher ALT values (especially higher than 120 Iu/mL at baseline) to LdT treatment. Adjustments for treatment strategy should be considered if HBV DnA > 300 copies/mL at Week 24 is observed.

Entecavir plus Adefovir Combination Treatment for Chronic Hepatitis B Patients after Failure of Nucleoside/Nucleotide Analogues

The combination of entecavir, a nucleoside analogue, and adefovir, a nucleotide analogue, would be a promising salvage treatment for chronic hepatitis B (CHB) patients who fail nucleoside/nucleotide analogue (NA) regimens. A total of 89 CHB patients who had failed NA regimens and were treated with entecavir plus adefovir combination for at least 12 months were included. Mean baseline HBV DNA of patients was 6.16 ±1.44 log(10) IU/ml. Patients were classed by the number of previously failed NAs; 1 NA (lamivudine; n=15; Group 1), 2 NAs (lamivudine and either adefovir or entecavir; n=39; Group 2) and 3 NAs (lamivudine, adefovir and entecavir; n=35; Group 3). After 12 months of treatment, the mean reduction in HBV DNA was greater in Group 1 than in Group 2 or 3 (-5.81 ±1.71, -3.20 ±1.36 and -2.93 ±1.56 log(10) IU/ml, respectively; P<0.01). The rates of virological response (HBV DNA<2,000 IU/ml) were 100%, 79.5% and 34.3% (P<0.01), and the rates of complete virological response (HBV DNA<60 IU/ml) were 53.3%, 25.6% and 14.3% in Group 1, 2 and 3, respectively (P<0.01) at 12 months. Higher baseline HBV DNA (odds ratio =0.59; P=0.02) and increasing number of previously failed NAs (P<0.01) were independently associated with a lower rate of complete virological response at 12 months. Entecavir plus adefovir combination treatment was effective in achieving virological response in CHB patients after failure of NAs. However, its effect progressively decreased as the number of previously failed NAs increased.

Effect and Predictive Elements for 52 Weeks’ Telbivudine Treatment on Naïve HBeAg positive Chronic Hepatitis B

Antiviral treatment with nucleoside analogs has been used for chronic hepatitis B (CHB). Each kind of nucleoside analog has its own characteristics and suitability for patients. Telbivudine (LdT, brand name: Sebivo, Beijing Novartis Pharma Ltd) is the newest nucleoside analog, with strong and rapid viral suppression. However, its resistance rate is relatively high during long-term application, due to low genetic barriers to resistance. So, it is necessary to increase the effect and reduce resistance with effective management, according to baseline factors and early on-treatment responses. To reveal possible predictive factors of the effect of telbivudine (LdT) treatment on naïve HBeAg-positive chronic hepatitis B (CHB) patients to optimize treatment. A total 71 naïve chronic hepatitis B (CHB) patients who met the inclusion criteria were enrolled. All patients were treated with LdT 600 mg Qd for at least 52 weeks. Multiple logistic regression analyses were done to investigate the predictive values of baseline factors and responses at Week 24. The reduction in hepatitis virus B (HBV) DNA level was 6.44 ± 2.38 lg copies/mL at Week 52 compared with baseline. The complete virus response (CVR), biochemical response (BR), serological response (SR), and drug resistance (DR) were 61.99%, 77.46%, 35.21%, and 8.45% respectively. By multiple regression analysis, baseline alanine aminotransferase (ALT) levels significantly affected CVR (P = 0.024, OR = 1.008), and baseline ALT and baseline HBV DNA levels were independent compact factors of SR (P = 0.012, OR = 1.007; P = 0.001, OR = 0.423). The differences in CVR, SR, and DR in patients with ALT > 120 Iu/mL compared with patients with ALT ≤ 120 Iu/mL were statistically significant. The differences in SR in patients with HBV DNA > 107 copies/mL compared with patients with HBV DNA ≤ 107 copies/mL were statistically significant. Additionally, CVR, BR, and SR were differed significantly between patients with HBV DNA lower than 300 copies/mL at Week 24 and patients with HBV DNA higher than 300 copies/mL (P = 0.000, P = 0.0016, and P = 0.000, respectively). There were more responders among naïve HBeAg-positive chronic hepatitis B patients with lower HBV DNA levels (especially lower than 107 copies/mL) and higher ALT values (especially higher than 120 Iu/mL at baseline) to LdT treatment. Adjustments for treatment strategy should be considered if HBV DNA > 300 copies/mL at Week 24 is observed.

Factors Predicting the Effi cacy of Adefovir Dipivoxil on Treatment-Naïve Chronic Hepatitis B Patients at 48 Weeks

Background/AimsTo reveal possible factors predicting the effect of adefovir dipivoxil (ADV) treatment on chronic hepatitis B (CHB) and optimize the utilization of ADV.MethodsIn total, 168 treatment-naïve CHB patients were enrolled, including 117 hepatitis B e antigen (HBeAg)-positive patients and 51 HBeAg-negative patients who met the inclusion criteria. All patients were treated with ADV 10 mg per day for 48 weeks. Multiple logistic regression analyses were used to investigate baseline factors, and responses at weeks 12 and 24 were analyzed as predictive values.ResultsMultiple regression analyses showed that baseline HBeAg status and HBV DNA levels significantly affected the virological response (VR) (p<0.05), baseline ALT levels were an independent predictor of serological response (SR) (p<0.05) and the body mass index (BMI) may affect the biochemical response (BR) (p<0.05). There was a statistically significant difference in the VR and SR between patients with a primary nonresponse (PNR) at week 12 and those with a VR at week 12 (p<0.01). Additionally, the VR was significantly different between patients with HBV DNA lower than 103 copies/mL at week 24 and those with greater than 103 copies/mL (p<0.01).ConclusionsPatients with negative HBeAg, lower HBV DNA levels and higher ALT values at baseline are more suitable for ADV treatment, whereas patients with lower BMIs may be more amenable to ALT normalization. Adjustments for treatment strategy should be considered if PNR at week 12 or HBV DNA ≥103 copies/mL at week 24 is observed.

Response to tenofovir monotherapy in chronic hepatitis B patients with prior suboptimal response to entecavir

Both entecavir (ETV) and tenofovir (TDF) are potent antiviral agents for hepatitis B virus (HBV). Suboptimal response (SOR) following antiviral therapy is associated with an increased risk of subsequent treatment failure and viral resistance. It remains unclear whether switching to TDF is a reasonable approach in patients with SOR to ETV treatment. This study was aimed to determine how HBV patients with SOR to ETV respond to TDF monotherapy. Data of patients with SOR to ETV (failure to achieve >1 log(10) HBV-DNA reduction during the last 24 weeks of ETV treatment) who were switched to TDF monotherapy during 2005 and 2010 were reviewed. Treatment adherence was assessed by pill-count. Fourteen patients (2.9%) were identified from a total cohort of 482 ETV-treated patients. All 14 patients were Chinese and were infected with HBV genotype C (71%) or B (29%). Nine patients were men, and the median age was 41.5 years (19-64). Twelve were treatment naïve (one lamivudine- and one peginterferon-experienced patient); 85.7% were HBeAg positive. The median baseline HBV-DNA was 7.55 (5.30-9.40) log(10) copies/mL, and 57% had abnormal serum alanine aminotransferase (ALT) levels. Precore and/or basal core promoter mutations were detected in four patients, whereas no genotypic resistance was detected at baseline and before switching to TDF. The median duration of ETV treatment was 64.5 (26-126) weeks. The median HBV-DNA at the time of switching to TDF was 3.69 (3.00-4.90) log(10) copies/mL. The median HBV-DNA reduction from baseline and during the last 6-month observation period prior to switching to TDF was 4.04 (0.51-6.06) log(10) and 0.43 (-0.09-1.13) log(10) copies/mL, respectively. After the switching to TDF, all 14 patients (100%) achieved undetectable HBV-DNA and ALT normalization within a median duration of 30 weeks. In 12 patients who were HBeAg positive, HBeAg seroconversion was observed in two patients after TDF treatment of 75- and 84-weeks duration. There was no virological breakthrough observed after switching to TDF with a median follow-up period of 50 (24-160) weeks. TDF treatment was safe and well tolerated. In conclusion, suboptimal response to ETV is rare (approximately 3%). TDF monotherapy is safe and very effective in the management of HBV patients with SOR to ETV.

PREDICTORS OF SUSTAINED RESPONSE TO INTERFERON-BASED THERAPY IN CHRONIC HEPATITIS B

Objective: IFN-based therapy induces long-term remission in ~20% of CHB-patients. Identification of predictors of treatment response can facilitate the clinical decision. Methods: 168 CHB-patients treated with IFN-based therapy were studied. Predictors of end-of-treatment response (ETR) and sustained response (SR) one-year post therapy were identified by non-parametric chi-square test and correlation analysis. Results: Low baseline HBV DNA ( 4xULN) were independent predictors of ETR. Low viral load was stronger predictor than high ALT level. If both factors coexist the probability of ETR was 92%. In HBeAg-negative subjects SR correlates significantly with age below 40 years, evidence of early viral response at 3 rd month, fibrosis stage F<3 (METAVIR) and prolongation of treatment duration. HBeAg-seroconversion up to 6-month post-therapy was the strongest predictor of SR in HBeAgpositive patients. Conclusion: More favorable results could be achieved by pretreatment selection according to patients’ age, baseline viral load, ALT and liver fibrosis. Extension of IFN-treatment in responders may enhance the SR rate.