Baseline Hepatitis B Virus DNA Research Articles

Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis

Seroclearance of hepatitis B surface antigen (HBsAg) is a marker for clearance of chronic hepatitis B virus (HBV) infection, but reported annual incidence rates of HBsAg seroclearance vary. We performed a systematic review and meta-analysis to provide more precise estimates of HBsAg seroclearance rates among subgroups and populations. We searched PubMed, Embase, and the Cochrane library for cohort studies that reported HBsAg seroclearance in adults with chronic HBV infection with more than 1 year of follow-up and at least 1 repeat test for HBsAg. Annual and 5-, 10-, and 15-year cumulative incidence rates were pooled using a random effects model. We analyzed 34 published studies (with 42,588 patients, 303,754 person-years of follow-up, and 3194 HBsAg seroclearance events), including additional and updated aggregated data from 19 studies. The pooled annual rate of HBsAg seroclearance was 1.02% (95% CI, 0.79-1.27). Cumulative incidence rates were 4.03% at 5 years (95% CI, 2.49-5.93), 8.16% at 10 years (95% CI, 5.24-11.72), and 17.99% at 15 years (95% CI, 6.18-23.24). There were no significant differences between the sexes. A higher proportion of patients who tested negative for HBeAg at baseline had seroclearance (1.33%; 95% CI, 0.76-2.05) than those who tested positive for HBeAg (0.40%; 95% CI, 0.25-0.59) (P < .01). Having HBsAg seroclearance was also associated with a lower baseline HBV DNA level (6.61 log10 IU/mL; 95% CI, 5.94-7.27) vs not having HBsAg seroclearance (7.71 log10 IU/mL; 95% CI, 7.41-8.02) (P < .01) and with a lower level of HBsAg at baseline (2.74 log10 IU/mL; 95% CI, 1.88-3.60) vs not having HBsAg seroclearance (3.90 log10 IU/mL, 95% CI, 3.73-4.06) (P< .01). HBsAg seroclearance was not associated with HBV genotype or treatment history. Heterogeneity was substantial across the studies (I2= 97.49%). In a systematic review and meta-analysis, we found a low rate of HBsAg seroclearance in untreated and treated patients (pooled annual rate, approximately 1%). Seroclearance occurred mainly in patients with less active disease. Patients with chronic HBV infection should therefore be counseled on the need for lifelong treatment, and curative therapies are needed.

Discontinuation of antiviral prophylaxis increased the risk of hepatitis B virus reactivation in glomerulonephritis patients under immunotherapy: a real-life observation.

Antiviral prophylaxis is proved to be effective in reducing the risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients under immunotherapy. But outcomes referring to discontinuation of antiviral prophylaxis in these patients are lacking. We performed a retrospective study of 105 HBsAg-positive patients under immunotherapy for glomerulonephritis and evaluated the incidence and risk factors for HBV reactivation. Among 105 patients, 55.24% completed antiviral prophylaxis, while 20.00% discontinued and 24.76% rejected antiviral prophylaxis. HBV reactivation was significantly different among completion, discontinuation, and rejection of antiviral prophylaxis: 5.17% versus 38.10% versus 15.38% in the incidence of HBV reactivation (P = 0.001), 3.45% versus 23.81% versus 11.54% in HBV DNA ≥ 5 Log copies/ml (P = 0.023), and 0 versus 14.29% versus 3.85% in hepatitis B e antigen seroconversion from negative to positive (P = 0.014). Survival curve showed the median occurrence time of HBV reactivation in discontinuation group was 32months (95% CI 24-39months), earlier than 69months (95% CI 65-72months) of completion group and 43months (95% CI 37-49months) of rejection group (χ2 = 13.780, P = 0.001). Univariate and multivariate analysis identified two independent risk factors for HBV reactivation: baseline HBV DNA detectable (OR 5.009, 95% CI 1.717-16.335, P = 0.012) and discontinuation of antiviral prophylaxis (OR 5.213, 95% CI 1.688-18.105, P = 0.011). Discontinuation of antiviral prophylaxis increased the risk of HBV reactivation in HBsAg-positive patients under immunotherapy for glomerulonephritis.

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Prevalence of Hepatitis B Reactivation Among Chinese Individuals With Chronic Hepatitis C Treated With Pan-Oral Direct-Acting Antivirals.

BackgroundClearance of hepatitis C virus (HCV) has been reported to induce the reactivation of hepatitis B virus (HBV). The aim of this study was to investigate the rate of HBV reactivation in HCV-infected Chinese patients who received treatment with pan-oral direct-acting antivirals (DAAs).MethodsData from HCV subjects receiving oral DAA therapy were retrospectively collected from October 2015 to May 2017. Patients who were seropositive for HBsAg or anti-HBc were enrolled. The efficacy of DAAs, including end-of-treatment virologic response (ETVR) and sustained virologic response (SVR) 12, was recorded. HBV virologic reactivation was defined as a reappearance of HBsAg, or increased HBV DNA by at least one log10 IU/mL. HBV clinical reactivation was defined as virologic reactivation and serum alanine aminotransferase (ALT) over two-fold of the upper limit of normal.ResultsThere were 11 (7.2%) cases and 53 (34.6%) cases in the HBsAg group and the anti-HBc group among all 153 subjects. All individuals achieved ETVR and SVR12. There were no cases with reappearance of HBsAg during DAAs therapy. Among seven cases in the HBsAg group whose HBV DNA level was determined, HBV virological reactivation was detected in two subjects (28.6%). Among all 11 subjects in the HBsAg group, there was one (9.1%) case with HBV clinical reactivation, which was resolved following treatment with Entaclavir. The case with HBV clinical reactivation had a higher baseline HBV DNA viral load (1,380 IU/mL) compared with that of the other patients (20 - 296 IU/mL).ConclusionHBV virological and clinical reactivation occurred in 28.5% and 9.1% of subjects with HBsAg seropositivity. No HBV reactivation was observed in the cases with past HBV infection.

Efficacy and Safety of Entecavir 0. 5 mg in Treating Naive Chronic Hepatitis B Virus Patients in Egypt: Five Years of Real Life Experience.

BackgroundThe aim of the study was to evaluate the efficacy and safety of entecavir (ETV) among chronic hepatitis B (CHB) nucleos(t)ide-naive Egyptian patients.MethodsForty-eight CHB patients on ETV were included. Males comprised 83.3% (40 cases), while females comprised 16.7% (eight cases). Minimum age was 19 years, while maximum age was 64 years. Hepatitis B envelope antigen (HBeAg)-negative cases were 60.4%. HBeAg-positive cases were 39.6%. Factors including sex, positive HBeAg, baseline hepatitis B virus (HBV) DNA level, baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were evaluated in terms of their predictive role in treatment response, which was defined as a serum HBV DNA decrease of < 10 IU/mL.ResultsMean age of patients was 38.2 years; males were 83.3% and females were 16.7%. HBeAg-negative cases were 60.4%, while HBeAg-positive cases were 39.6%. Mean baseline DNA level was 44 × 106 IU/mL. Ultrasound results showed 14 cases had hepatomegaly, 10 cases had bright liver, seven cases had coarse liver, and eight cases had cirrhosis. Of the cases, 45.8% showed a negative PCR after the first 6 months of therapy to reach 64.6% by the end of the first year. HBV DNA undetectability reached 91.3% and 100% after 4 and 5 years, respectively for those who completed the study period. ALT reduction started after 6 months of treatment and reached 53.37% after 5 years. Similarly AST showed the same pattern of decline and reached 54.37% after 5 years. Only two cases achieved HBeAg seroconversion. Three patients experienced virological breakthrough and the three cases shared similar characteristics of being less than 40 years, with baseline HBV DNA of ≥ 105 IU/mL and positive HBeAg. None of the cases showed hepatitis B surface antigen (HBsAg) seroconversion.ConclusionETV proved to have a potent antiviral efficacy and safety in nucleoside/tide-naive Egyptian patients. Rate of HBV DNA undetectability was higher in patients above 40 years of age and in patients who initially had a low viral load. ETV was well tolerated during the treatment period with a good overall safety profile.

Low incidence of hepatitis B virus reactivation and subsequent hepatitis in patients with chronic hepatitis C receiving direct-acting antiviral therapy.

To determine the clinical characteristics of hepatitis B virus (HBV) reactivation in patients undergoing interferon-free antihepatitis C virus (HCV) therapy, we examined HBV DNA in 25 HBV co-infected patients and 765 patients with resolved HBV infection during and after treatment with direct-acting antiviral agents (DAAs). Among those with HCV genotype 1, asunaprevir plus daclatasvir was administered to 160 patients, sofosbuvir (SOF) plus ledipasvir to 438 patients and paritaprevir plus ombitasvir and ritonavir to 25 patients. In total, 167 patients with genotype 2 were treated with SOF plus ribavirin. Three patients with an HBV DNA level ≥2000IU/mL were treated with entecavir before anti-HCV therapy, without reactivation of HBV. In 3 of 22 (12%) HBV surface antigen (HBsAg)-positive patients with an HBV DNA level <2000IU/mL, the viral load increased during treatment. However, hepatitis flare did not occur in these patients. There was no significant difference in clinical history between patients with and without HBV reactivation. Among 765 patients with resolved HBV infection, HBV reactivation occurred in 1 (0.1%) patient after initial resolution, whose HBV DNA level spontaneously decreased after DAA therapy. We compared anti-HBs titres at baseline with those at post-DAA therapy in 123 patients without HBsAg. There was no significant difference in anti-HBs levels between the two points (P=.79). In conclusion, HBV reactivation was rare in HBsAg-negative patients treated with DAA therapy. Additionally, hepatitis did not occur in HBV-reactivated patients with a baseline HBV DNA level <2000IU/mL before DAA therapy.

Safety and efficacy of telbivudine in late pregnancy to prevent mother-to-child transmission of hepatitis B virus: A multicenter prospective cohort study.

Infection of hepatitis B virus (HBV) occurs in ~10% of infants of HBV-infected mothers with positive hepatitis B e antigen (HBeAg) after immunoprophylaxis. We aimed to evaluate the safety and efficacy of telbivudine used during late pregnancy for preventing mother-to-child transmission of HBV. We conducted a multicenter prospective cohort study in 5 hospitals from 2012 to 2014, which enrolled HBV-infected singleton pregnant women with positive HBeAg. By their choice, women were divided into therapy (telbivudine 600mg/day, from gestation 28-32weeks to 3-4weeks postpartum) and control (no antiviral agent) groups. Infants received passive-active immunoprophylaxis and follow-up at the age of 7-14months. Totally, 328 pregnant women were included: 149 in the telbivudine group and 179 in the control group. Baseline HBV DNA levels were similar in the 2 groups (7.43 vs 7.37 log10 IU/mL, P=.711). At delivery, HBV DNA levels in the telbivudine and control groups were 3.80 and 7.26 log10 IU/mL, respectively (P<.0001). Of the infants, 128 (85.9%) in the telbivudine group and 156 (87.2%) in the control group were followed up. No infant in the telbivudine group had chronic infection, while 2 (1.28%) infants in the control group did (P=.503). Three (2.34%) infants in the telbivudine group, but none in the control group, had severe congenital or developmental abnormalities (P=.090). The data indicate that telbivudine may block perinatal HBV transmission. However, larger studies are required to clarify whether anti-HBV therapy in pregnancy is associated with severe adverse effects in the foetuses and infants.

Infección crónica por virus de la hepatitis B antígeno e negativo. Manejo en función de puntos de corte de glutámico-pirúvica transaminasa y ácido desoxirribonucleico del virus de la hepatitis B

ObjectivesTo identify glutamic pyruvic transaminase (GPT) and hepatitis B virus DNA (HBV-DNA) cut-off values at diagnosis in patients with hepatitis B virus e antigen-negative chronic infection (HBeAg(–)), which may be predictors of clinical course, prognosis and/or the need for antiviral therapy. MethodsA retrospective and observational cohort study of patients diagnosed with HBeAg(–) chronic infection (2005-2012). A normal GPT cut-off value at diagnosis that predicts abnormal GPT values in the clinical course of the infection, a baseline HBV-DNA cut-off value that predicts an increase in HBV-DNA above 2,000IU/ml, and GPT and HBV-DNA as predictors of the need for treatment were investigated using ROC curves. Results126 patients were enrolled (follow-up: 42.1±21.5months), 93 of which had normal GPT levels at diagnosis. In the ROC curve analysis, 900IU/ml was found to be the HBV-DNA cut-off value that best predicted this value's increase above 2,000IU/ml (sensitivity: 90%; specificity: 88%; PPV: 79%; NPV: 100%; diagnostic precision: 89%), while 25mU/ml was the normal GPT cut-off value at diagnosis that best predicted subsequently elevated GPT levels (sensitivity: 95.4%; specificity: 81.6%; PPV: 67%; NPV: 96%; diagnostic precision: 80.6%). Patients with GPT 26-40mU/ml at diagnosis presented with more complications or required more treatment than subjects with GPT≤25mU/ml (P<.05). The combined GPT and HBV-DNA values that elicited the highest treatment need were 38mU/ml of GPT and 6,000IU/ml of HBV-DNA (sensitivity: 75%; specificity: 93.4%; PPV: 60%; NPV: 96.6%). ConclusionHBeAg(–) patients with GPT<25mU/ml and HBV-DNA<900IU/ml at diagnosis have positive outcomes and may not require such stringent follow-up in the first years after diagnosis.

Efficacy of Ledipasvir and Sofosbuvir Treatment of HCV Infection in Patients Coinfected With HBV

There have been reports of reactivation of hepatitis B virus (HBV) infection during treatment of hepatitis C virus (HCV) infection with direct-acting antiviral agents. We performed a prospective study of risks and outcomes of HCV infection treatment with ledipasvir and sofosbuvir in patients with HBV infection. We performed a phase 3b, multicenter, open-label study in Taiwan of 111 patients with HCV infection (61% HCV genotype 1, 39% HCV genotype 2 infection; 62% women, 16% with compensated cirrhosis) along with HBV infection. All but 1 were positive for the hepatitis B surface antigen (HBsAg); 1 patient who was HBsAg-positive at screening was found to be HBsAg-negative at baseline. Overall, 33% of participants had received prior treatment for HCV and 5% had previously been treated for HBV; no patient was on HBV therapy at the start of the study. All patients received a fixed-dose combination of 90 mg of the HCV NS5A inhibitor ledipasvir with 400 mg of the NS5B nucleotide analogue inhibitor sofosbuvir, once daily for 12 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of therapy. All 111 patients (100%) achieved a sustained virologic response. Of the 37 patients with baseline HBV DNA below 20 IU/mL, 31 (84%) had at least 1 episode of quantifiable HBV DNA through posttreatment week 12. Of the 74 patients with baseline HBV DNA levels of 20 IU/mL or more, 39 (53%) had increases of HBV DNA greater than 1 log10 IU/mL through posttreatment week 12. Overall, 5 patients had increased levels of HBV DNA concomitant with a level of alanine aminotransferase >2 times the upper limit of normal through posttreatment week 12. Of these, 3 patients started HBV treatment. In addition, 1 patient with HBV reactivation since week 8 and concomitant alanine aminotransferase elevation >2 times upper limit of normal at posttreatment week 48 started treatment at posttreatment week 53. This patient had clinical signs and symptoms associated with HBV reactivation. The most common adverse events were headache, upper respiratory infection, and fatigue. In a prospective study, the combination of ledipasvir and sofosbuvir for 12 weeks produced a sustained virologic response in 100% of patients with HCV infection who were coinfected with HBV. Most patients had an increase in level of HBV DNA not associated with signs or symptoms. ClinicalTrials.gov no: NCT02613871.

The effect of antiviral therapy on patients with hepatitis B virus-related hepatocellular carcinoma after curative resection: a systematic review and meta-analysis.

Background and aimStudies suggest that antiviral therapy performed after curative resection improves the postoperative prognosis of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), but the evidence has been contradictory. The aim of this meta-analysis was to assess the effect of antiviral therapy with nucleoside analogs (NAs) after curative resection on the long-term postoperative survival of patients with HBV-related HCC.Materials and methodsMEDLINE, PubMed, Embase, and Cochrane Library were systematically searched up to August 2017 with no limits. Outcome measures were the primary parameter of overall survival (OS) after radical resection of HBV-related HCC and the secondary parameter of postoperative recurrence-free survival (RFS).ResultsA total of 9,009 patients (2,546 of whom received antiviral therapy and 6,463 received no treatment) were included. The pooled analysis revealed that antiviral therapy was associated with significantly improved OS (hazard ratio [HR]: 0.58; 95% confidence interval [CI]: 0.51–0.67; P<0.00001) and RFS (HR: 0.68; 95% CI: 0.63–0.74; P<0.00001). Moderate heterogeneity among studies for both OS and RFS was observed, which disappeared or decreased after pooling studies using one type of NA as antiviral drug. In the subgroup analysis, anti-viral therapy significantly prolonged both OS (HR: 0.69; 95% CI: 0.52–0.92; P=0.01) and RFS (HR: 0.58; 95% CI: 0.49–0.70; P<0.00001) in patients with high baseline HBV DNA level (≥20,000 IU/mL) with no heterogeneity, but not in patients with low baseline HBV DNA level (<20,000 IU/mL).ConclusionAntiviral therapy with NAs confers significant survival benefits in patients with HBV-related HCC after curative resection, especially in patients with high baseline HBV DNA level (≥20,000 IU/mL).

Accumulation of mutations in reverse transcriptase of hepatitis B virus is associated with liver disease severity in treatment-naïve Chinese patients with chronic hepatitis B.

Mutations in reverse transcriptase (RT) of the hepatitis B virus (HBV) are demonstrated to be strongly associated with nucleos(t)ide analog resistance, which is supposed to be the biggest obstacle during the long-term anti-viral treatment of chronic hepatitis B. However, the presence of RT mutations in treatment-naïve chronic hepatitis B patients and its clinical significance are not well known. To investigate the significance of mutations in reverse transcriptase of the hepatitis B virus in treatment-naïve Chinese patients with chronic hepatitis B. In this study, 288 treatment-naïve chronic HBV patients were recruited and the RT region was sequenced. The results showed that 71 patients (24.65%) were found with RT mutations, within which there were no well-defined primary nucleotide analog-resistant mutations. There were a total of 28 mutant sites, which formed three dominant mutant clusters: rt124-139, rt191-212 and rt225-229. Among these 71 patients, 63.38% (45/71) of patients had a single mutation while 19.72% (14/71), 12.68% (9/71) and 4.23% (3/71) of patients had 2, 3 or 4 mutations, respectively. Patients with RT mutations showed significantly decreased serum baseline HBV DNA loads (p = 0.0363) and blood platelet count (p = 0.0181) than patients without RT mutations. Patients with multiple mutant sites (≥ 2) had significantly decreased baseline HBV DNA loads (p = 0.0004) and blood platelet count (p = 0.0011) than patients with single mutant site. Moreover, the number of RT mutant sites is significantly associated with severity of liver fibrosis (p = 0.0128). This study demonstrated that there was a prevalence of RT mutations in treatment-naïve chronic hepatitis B patients, which reflects a tougher liver environment for the virus and deeper liver injury for the host. Accumulation of RT mutations was associated with liver disease severity in treatment-naïve chronic hepatitis B patients.

Dynamics of the Immune Response in Acute Hepatitis B Infection.

BackgroundAcute hepatitis B virus infection in adults is generally self-limiting but may lead to chronicity in a minority of patients.MethodsWe included 9 patients with acute hepatitis B virus (HBV) infection and collected longitudinal follow-up samples. Natural killer (NK) cell characteristics were analyzed by flowcytometry. HBV-specific T-cell function was analyzed by in vitro stimulation with HBV peptide pools and intracellular cytokine staining.ResultsMedian baseline HBV DNA load was 5.12 log IU/mL, and median ALT was 2652 U/mL. Of 9 patients, 8 cleared HBsAg within 6 months whereas 1 patient became chronically infected. Early time points after infection showed increased CD56bright NK cells and an increased proportion of cells expressing activation markers. Most of these had normalized at week 24, while the proportion of TRAIL-positive CD56bright NK cells remained high in the chronically infected patient. In patients who cleared HBV, functional HBV-specific CD8+ and CD4+ responses could be observed, whereas in the patient who developed chronic infection, only low HBV-specific T-cell responses were observed.ConclusionsNK cells are activated early in the course of acute HBV infection. Broad and multispecific T-cell responses are observed in patients who clear acute HBV infection, but not in a patient who became chronically infected.

Correlation of Quantitative Assay of HBsAg and Hepatitis B Virus DNA Levels Among Chronic HBV Patients Attending Pathologist Lancet Laboratory in Nairobi, Kenya

Background: Hepatitis B Virus (HBV) viral load measurements is recommended for diagnosis and monitoring of patients on treatment for Chronic Hepatitis B (CHB). However, these diagnostic techniques are molecular-based and expensive and unavailable to majority of the Kenyan population. Quantitation of hepatitis B surface antigen (HBsAg) by automated chemiluminescent micro-particle immunoassay has been proposed as a surrogate marker. Objectives: This study showed the correlation between HBsAg and HBV DNA levels among patients with CHB attending a referral Laboratory in Nairobi, Kenya. Methods: One hundred and seventy-three (173) patients were enrolled while excluding Hepatitis C Virus (HCV) and Hepatitis D Virus (HDV) positive patients. Results: The mean age of the study patients was 37.2 years, 112 (64.7%) were male, and 142 (82.1%) were hepatitis B e antigen (HBeAg) negative while 31/173 (17.9%) were HBeAg positive. The mean HBV DNA level was 2.89 log10 IU/mL and 41 (23.7%) had a baseline HBV DNA level of > 2000 IU/mL. By Mann-Whitney test, HBV DNA levels differed significantly between HBeAg positive and negative patients (P = 0.001), as did HBsAg titer (P = 0.032). Unfortunately, according to the Spearman test, there was a weak correlation between HBsAg and HBV DNA levels (P = 0.024 and r = 0.171). Conclusions: Patients with HBeAg negative test results had lower levels of HBsAg and lower levels of HBV DNA. Serum quantitation of HBsAg may not replace serum HBV DNA levels among patients with CHB in Nairobi Kenya.

Cirrhosis has no impact on therapeutic responses of entecavir for chronic hepatitis B.

As the efficacy of a direct antiviral agent is reduced in cirrhotic chronic hepatitis C patients, prolonged duration of treatment or addition of ribavirin is recommended to improve the rates of sustained virological response. However, the impact of cirrhosis on the efficacy of antiviral treatment for chronic hepatitis B (CHB) remained unclear. This retrospective cohort study screened entecavir (ETV)-treated CHB patients in Taipei Tzu Chi Hospital from January 2007 till October 2014. The diagnosis of cirrhosis was made on the basis of clinical/imaging or histologic findings. The primary endpoints were hepatitis B e antigen (HBeAg) loss in HBeAg-positive patients and undetectable hepatitis B virus (HBV) DNA in the overall study population. Initial virological response is defined as undetectable HBV DNA at 1-year ETV treatment. A total of 381 (262 men; mean age: 49.6±12.9 years) CHB patients were recruited for the final analysis. Of these, 138 were cirrhotic. In 143 HBeAg-positive patients, there was no difference in the rates of 1- and 2-year HBeAg loss between cirrhotic and noncirrhotic patients (P=0.226 and 0.729, respectively). In the overall population, the rate of 1-year undetectable HBV DNA was higher in patients with cirrhosis than those without cirrhosis (76.1 vs. 64.2%, P=0.016). The rate of 2-year undetectable HBV DNA was not different between these two groups. Using multivariate logistic regression analysis, baseline HBV DNA levels (P=0.006) and HBeAg status (P=0.007), were associated with initial virological response, but not cirrhosis. Therapeutic responses of ETV are not decreased in cirrhotic CHB patients. Thus, cirrhotic CHB patients can be treated with ETV without the need for dose adjustment.

Efficacy of tenofovir-based rescue therapy for chronic hepatitis B patients with resistance to lamivudine and entecavir.

Background/AimsTenofovir disoproxil fumarate (TDF) monotherapy for 48 weeks provided a virological response comparable to that of TDF and entecavir (ETV) combination therapy in patients infected with ETV-resistant hepatitis B virus (HBV). Little long-term data in routine clinical practice are available regarding the optimal treatment of patients with ETV-resistant HBV.MethodsWe investigated the long-term antiviral efficacy of combination therapy of TDF+lamivudine (LAM) or TDF+ETV compared to that of TDF monotherapy in 73 patients with resistance to both LAM and ETV.ResultsPatients were treated with TDF monotherapy (n=12), TDF+LAM (n=19), or TDF+ETV (n=42) for more than 6 months. The median duration of TDF-based rescue therapy was 37 months. Virologic response (VR) was found in 63 patients (86.3%). The rates of VR among the three groups (TDF monotherapy, TDF+LAM, and TDF+ETV) were not statistically different (log-rank P=0.200) at 12 months (59.3%, 78.9%, and 51.8%, respectively) or at 24 months (88.4%, 94.7%, and 84.2%). In addition, treatment efficacy of TDF-based combination or TDF monotherapy was not statistically different with ETV-resistant strains or exposure to other antiviral agents. In multivariate analysis, only lower baseline HBV DNA level was an independent predictor for VR (hazard ratio, 0.723; 95% confidence interval, 0.627-0.834; P<0.001).ConclusionsTDF monotherapy was as effective as combination therapy of TDF+LAM or TDF+ETV in maintaining long-term viral suppression in chronic hepatitis B patients with resistance to both LAM and ETV. HBV DNA level at the start of TDF rescue therapy was the only independent predictor of subsequent VR.

Predictive value of platelet to lymphocyte ratio for early virological response in patients with genotype C hepatitis B virus infection who were treated with Entecavir

Objective To investigate the prognostic value of platelet to lymphocyte ratio (PLR) for early virological response in Entecavir (ETV)-treated chronic hepatitis B (CHB) patients with genotype C infection. Methods Ninety-one genotype C CHB patients with HBV DNA≥1×105 copies/mL were treated with ETV (0.5 mg/d) for 10—13 days. The correlation between PLR and viral load decline was evaluated by Pearson or Spearman′s rank correlation coefficient. Stepwise linear regression analysis was used to establish the prediction model of virological response. Receiver operating characteristic (ROC) curves were used to evaluate the predictive value of PLR for early virological response in ETV-treated patients with genotype C hepatitis B virus (HBV) infection. Results After 10—13 days of ETV treatment, HBV DNA decreased ≥1×lg copies/mL from baseline in 89 cases of the 91 patients, while HBV DNA declined ≥2×lg copies/mL in 65 patients and 4 patients achieved HBV DNA<500 copies/mL. HBV DNA decline was positively correlated with baseline PLR levels (r=0.235 09, P<0.05). After adjustment for age, gender, Hepatitis B e Antigen (HBeAg), and treatment days, HBV DNA decline was still positively correlated with baseline PLR levels (r=0.220 26, P<0.05). Area under curve (AUC) of prediction model including age , baseline aspartate transaminase (AST) and HBV DNA was 0.759 (95% CI : 0.660—0.859, P<0.01). After adding PLR to the prediction model, the AUC was 0.780 (95% CI: 0.685—0.875, P<0.01). Conclusions PLR is predictive to early virological response in ETV-treated CHB patients with genotype C infection. Higher baseline PLR level indicates a better virological response. PLR monitoring should be recommended in CHB patients with antiviral treatment in clinical practice. Key words: Hepatitis B, chronic; HBV DNA; Entecavir; Forecasting; PLR

Entecavir Combined With Adefovir Ameliorates Patients With Chronic Hepatitis B Who Fail to Respond to Nucleotide (Acid) Analog Monotherapy.

The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 ± 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean ± SEM, which were 1.53 ± 1.23, 1.75 ± 1.37, 2.07 ± 1.54, and 2.39 ± 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (χ = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment.

Tenofovir has inferior efficacy in adefovir-experienced chronic hepatitis B patients compared to nucleos(t)ide-naïve patients.

Background/AimsA recent study reported that entecavir had inferior efficacy in nucleos(t)ide analogue (NA)-experienced chronic hepatitis B (CHB) patients compared to NA-naïve patients. We sought to compare the efficacy of tenofovir disoproxil fumarate (TDF) in NA-experienced and NA-naïve CHB patients.MethodsWe retrospectively enrolled 252 consecutive patients who had a serum hepatitis B virus (HBV) DNA level greater than 2,000 IU/mL at the initiation of TDF treatment and who received TDF for at least 6 months. Complete virologic suppression (CVS) was defined as undetectable serum HBV DNA. We generated a multivariate Cox proportional-hazard model to examine predictive factors that were independently associated with time to CVS.ResultsThe mean age of patients was 48.2 years, and the cohort included 181 NA-naïve patients and 71 NA-experienced patients. The median duration of TDF treatment was 14.4 (interquartile range, 9.5-17.8) months. A total of 167 (92.3%) of 181 NA-naïve patients achieved CVS, and 60 (84.5%) of 71 NA-exposed patients achieved CVS. Forty-nine (89.1%) of 55 patients who previously took an NA aside from adefovir and 11 (68.8%) of 16 adefovir-experienced patients achieved CVS. In multivariable analysis, previous adefovir exposure significantly influenced time to CVS (hazard ratio, 0.37; 95% confidence interval, 0.19-0.72; P=0.003), after adjusting for HBeAg positivity, baseline HBV DNA level and cirrhosis.ConclusionsTenofovir had inferior efficacy in adefovir-experienced CHB patients compared to NA-naïve patients. The response of patients with previous adefovir exposure to TDF monotherapy should be monitored closely.

Telbivudine therapy for chronic hepatitis B: A journey to identify super-responders and to optimize treatment using the roadmap model.

Hepatitis B virus (HBV) infection is one of the most serious health problems worldwide with a high risk for cirrhosis and liver cancer. Several antiviral agents have been approved for the treatment of chronic hepatitis B, leading to a rapid reduction in HBV DNA and normalization of serum alanine aminotransferase levels. Telbivudine, a potent inhibitor of HBV replication, has been shown to be well tolerated. Because of the emergence of drug resistance, optimization strategies for telbivudine therapy have been shown to improve patient responses. Optimal baseline characteristics in so-called super-responders have been used to predict the virological response. Baseline HBV DNA levels < 9 log10 copies/mL (2 × 108 IU/mL) or alanine aminotransferase levels of more than or equal to twofold the upper limit of normal in HBeAg-positive patients and HBV DNA < 7 log10 copies/mL (2 × 106 IU/mL) in HBeAg-negative patients were strong predictors for virological response. In addition, the roadmap model, based on early virological response at week 24 of therapy, is considered as a powerful tool to identify patients at risk of treatment failure (HBV DNA ≥ 300 copies/mL, i.e. 60 IU/mL) and to reduce the risk of antiviral resistance. When considering pre-treatment characteristics and on-treatment responses, telbivudine may provide physicians with a wide choice of options to effectively treat patients with chronic hepatitis B, especially those with or at risk of renal impairment, or women of childbearing age.

Efficacy and safety of tenofovir in chronic hepatitis B: Australian real world experience.

AIMTo evaluate the long-term treatment outcomes of tenofovir therapy in patients in a real world Australian tertiary care setting.METHODSWe performed a retrospective analysis of treatment outcomes among treatment-naïve and treatment-experienced patients receiving a minimum 3 mo tenofovir therapy through St Vincent’s Hospital Melbourne, Australia. We included patients receiving tenofovir [tenofovir disoproxil fumarate (TDF)] monotherapy, as well as patients treated with TDF in combination with a second antiviral agent. Patients were excluded if they demonstrated human immune-deficiency virus/hepatitis C virus/hepatitis delta virus coinfection or were less than 18 years of age. We considered virological and biochemical response, as well as safety outcomes. Virological response was determined by measurement of hepatitis B virus (HBV) DNA using sensitive assays; biochemical response was determined via serum liver function tests; histological response was determined from liver biopsy and fibroscan; safety analysis focused on glomerular renal function and bone mineral density. The primary efficacy endpoint was complete virological suppression over time, defined by HBV DNA < 20 IU/mL. Secondary efficacy endpoints included rates of biochemical response, and HB e antigen (HBeAg)/HB surface antigen loss and seroconversion over time.RESULTSNinety-two patients were identified who fulfilled the enrolment criteria. Median follow-up was 26 mo (range 3-114). Mean age was 46 (24-78) years, 64 (70%) were male and 77 (84%) were of Asian origin. 55 (60%) patients were treatment-naïve and 62 patients (67%) were HBeAg-negative. Complete virological suppression was achieved by 45/65 (71%) patients at 12 mo, 37/46 (80%) at 24 mo and 25/28 (89%) at 36 mo. Partial virological response (HBV DNA 20-2000 IU/mL) was achieved by 89/92 (96.7%) of patients. Multivariate analysis showed a significant relationship between virological suppression at end of follow-up and baseline HBV DNA level (OR = 0.897, 95%CI: 0.833-0.967, P = 0.0046) and HBeAg positive status (OR = 0.373, 95%CI: 0.183-0.762, P = 0.0069). There was no difference in response comparing treatment-naïve and treatment-experienced patients. Three episodes of virological breakthrough occurred in the setting of non-compliance. Tenofovir therapy was well tolerated.CONCLUSIONTenofovir is an efficacious, safe and well-tolerated treatment in an Australian real-world tertiary care setting. Our data are similar to the reported experience from registration trials.