Faculty Bibliography

Of the estimated 400 million patients with chronic hepatitis B (CHB) globally, around 75% are Asians, representing a clinically important sub-group with a higher risk of cirrhosis and hepatocellular carcinoma than Caucasian patients. This review summarizes recent data from clinical long-term and real-life studies of entecavir and tenofovir, the recommended first-line oral therapies for treating CHB, in nucleos(t)ide-naive Asian CHB patients with compensated or decompensated liver disease. Long-term treatment with entecavir or tenofovir achieved profound and durable virological suppression, and led to improved liver histology and function. The data presented in this review will help physicians in making evidence-based decisions choices regarding first-line antiviral therapy and long-term management in Asian CHB patients.

AIMS: Hepatitis B virus (HBV) reverse transcriptase (RT) mutants, which have not been well characterized according to different disease stages. This study aimed to characterize the profiles of naturally occurring mutations in the HBV RT region and their associated clinical outcomes. METHODS: HBV RT region mutations and genotypes were determined by PCR-direct sequencing and compared with p-distance model. RESULTS: Among 467 consecutive eligible patients (262 chronic hepatitis B patients, 105 cirrhotic patients and 100 hepatocellular carcinoma patients), the nucleos(t)ide analogues-related mutations (rtI169T, rtV173L, rtL180M, rtA181T, rtS202C, rtM204I/V, rtN236T) were found. The p-distance value reached a peak in the age of 20-30 years in the CHB patients and in the age of 40-45 years in the cirrhotic patients and hepatocellular carcinoma patients. The naturally occurring mutation, rtS106C mutation was higher in chronic hepatitis B patients (14/100, 14.0%) and cirrhotic patients (14/100, 14.0%) than that in hepatocellular carcinoma patients (4/100, 4.0%, P = 0.013). And the rtD134E/G/N/S mutations were also higher in chronic hepatitis B patients (22/100, 22.0%) and cirrhotic patients (21/100, 21.0%) than that in hepatocellular carcinoma patients (10/100, 10.0%, P = 0.021 and P = 0.032 respectively). The mutation frequencies in A-B interdomain were higher in cirrhotic patients (101/1900, 5.3%) than that in hepatocellular carcinoma patients (68/1900, 3.6%) (P = 0.009). CONCLUSIONS: The nucleos(t)ide analogues-related mutations do exist in treatment naive patients with different disease stages. rtS106C, rtD134E/G/N/S and A-B interdomain mutations may be associated with necro-inflammation, immune response and cirrhosis development at ages older than 40.

BACKGROUND: Despite appropriate immunoprophylaxis, up to 10 % of infants born to highly viremic hepatitis B virus (HBV-DNA >/= 7 log IU/mL) mothers are infected with HBV. Use of TDF to prevent vertical transmission (VT) by such mothers has not been evaluated. PURPOSE: To evaluate the efficacy and safety of TDF in preventing VT from highly viremic HBV-infected mothers. METHODS: Data were collected retrospectively from HBV mono-infected, hepatitis B e antigen (HBeAg) positive, pregnant women between 6/2008 and 11/2010. Cases enrolled were HBV mono-infected mothers who received TDF (300 mg orally once a day) in the third trimester. Those with pregnancy complications or an abnormal fetus on sonography were excluded from use of TDF. All infants received hepatitis B immunoglobulin and vaccination at birth and subsequently. RESULTS: Eleven Asian mothers received TDF at the median gestational age of 29 (28-32) weeks and the median duration of TDF use before delivery was 10 (7-12) weeks. A significant reduction in serum HBV-DNA was achieved at delivery compared with baseline (mean 5.25 +/- 1.79 vs. 8.87 +/- 0.45 log(10) copies/mL, respectively; p < 0.01). Three had serum ALT levels more than 1.5 times the upper limit of normal and two of these normalized before delivery. The 11 infants were born with no obstetric complication or birth defects. Five infants were breastfed. All infants were hepatitis B surface antigen negative 28-36 weeks after birth. CONCLUSION: Our preliminary data suggest that TDF use in the third trimester is safe, and effectively prevents VT of HBV from high viremic HBeAg-positive mothers.

There are limited data on the effects of long-term entecavir therapy in Asian patients with chronic hepatitis B (CHB). We performed a post hoc analysis of 94 Asian hepatitis B e antigen-positive (HBeAg+), nucleos(t)ide analogue-naive patients who received 5 years of therapy with entecavir (up to 2 years in study ETV-022 and the remainder in study ETV-901). Among patients completing week 240, 95% (63 of 66) had levels of hepatitis B virus DNA <300 copies/mL, and 76% (50 of 66) had normalized levels of alanine aminotransferase. In addition to patients who achieved a serologic response during ETV-022, a further 40% (26 of 65) achieved HBeAg loss, and 18% (12 of 65) underwent HBeAg seroconversion through year 5 of entecavir therapy. No resistance to entecavir was detected, and the safety profile was consistent with previous reports. The long-term efficacy and safety of entecavir are therefore comparable between Asians and the overall population of HBeAg+ patients with CHB.

BACKGROUND & AIMS: Telbivudine reduces hepatitis B virus (HBV) DNA and normalizes levels of alanine aminotransferase (ALT) in patients with chronic hepatitis B (CHB). We investigated its use in preventing vertical transmission. METHODS: We performed an open-label, prospective study of 88 hepatitis B (HB) e antigen (HBeAg)-positive pregnant women with CHB, levels of HBV DNA >6 log(10) copies/mL, and increased levels of ALT. Women were given telbivudine (n = 53) starting in the 2nd or 3rd trimester, or no treatment (controls, n = 35) and followed until postpartum week (PPW) 28. All infants received standard immunoprophylaxis after birth. RESULTS: At 28 weeks, none of the infants whose mothers received telbivudine had immunoprophylaxis failure, whereas 8.6% of the infants of control mothers did (P = .029). There were no differences between groups in mothers' adverse events or infants' congenital deformities, gestational age, height, and weight, or Apgar scores. At postpartum week 28, significantly more telbivudine-treated mothers had levels of HBV DNA <500 copies/mL, normalized levels of ALT, and hepatitis B e antigen seroconversion compared with controls (58% vs none, P < .001; 92% vs 71%; P = .008; and 15% vs none; P < .001, respectively) but none had loss of hepatitis B surface antigen. Telbivudine-treated mothers had no virologic breakthrough (HBV DNA >1 log(10) increase from <500 copies/mL) or discontinuations from adverse events. After delivery, 13/52 patients discontinued telbivudine due to preference. There were no episodes of severe hepatitis (levels of ALT >10 times the upper limit of normal) in either group during 28 weeks of postpartum observation. CONCLUSIONS: Women with CHB given telbivudine during the second or third trimester of pregnancy have reduced rates of perinatal transmission. Telbivudine produced no adverse events in mothers or infants by 28 weeks.

BACKGROUND & AIMS: Despite immunoprophylaxis, mother to child transmission (MTCT) of hepatitis B virus (HBV) still occurs in infants born to hepatitis B surface antigen (HBsAg)-positive mothers. We analyzed methods of risk assessment and interventions for MTCT. METHODS: We reviewed 63 articles and abstracts published from 1975-2011 that were relevant to MTCT; articles were identified using the PubMed bibliographic database. RESULTS: Administration of HB immunoglobulin and HB vaccine to infants at birth (within 12 hours), followed by 2 additional doses of vaccines within 6-12 months, prevented approximately 95% of HBV transmission from HBsAg-positive mothers to their infants. However, HBV was still transmitted from 8%-30% of mothers with high levels of viremia. It is important to assess the risk for MTCT and identify mothers who are the best candidates for intervention. The most important risk factor is maternal level of HBV DNA >200,000 IU (10(6) copies)/mL; other factors include a positive test result for the HB e antigen, pregnancy complications such as threatened preterm labor or prolonged labor, and failure of immunoprophylaxis in prior children. Antiviral therapy during late stages of pregnancy is the most effective method to reduce transmission from mothers with high levels of viremia, but elective cesarean section might also be effective. Antepartum administration of HB immunoglobulin, giving infants a double dose of HB vaccine, or avoiding breastfeeding had no impact on MTCT. CONCLUSIONS: HBsAg-positive mothers should be assessed for risk of MTCT, and infants should receive immunoprophylaxis. Pregnant women with levels of HBV DNA >200,000 IU/mL should be considered for strategies to reduce the risk for MTCT. We propose an algorithm for risk assessment and patient management that is based on a review of the literature and the opinion of a panel of physicians with expertise in preventing MTCT.

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 naive (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.

In infants born to hepatitis B surface antigen (HBsAg)-positive mothers, failure after passive-active immunization still occurs. The role of maternal hepatitis B DNA level and other risk factors in this setting remains unclear. This study retrospectively evaluated virologic and other risk factors associated with immunoprophylaxis failure in infants born to HBsAg-positive mothers. Between January 2007 and March 2010, we reviewed the clinical and virologic tests in 869 mother-infant pairs. All infants received the identical passive-active immunization schedule after birth. The failure infants (HBsAg positive at 7-12 months of age) were compared to infants who were HBsAg negative when tested during this time period. Among 869 infants, 27 (3.1%) infants were immunoprophylaxis failures and the other 842 (96.9%) infants remained HBsAg negative. When mothers' pre-delivery HBV DNA levels were stratified to <6, 6-6.99, 7-7.99 and >/= 8 log(10) copies/mL, the corresponding rates of immunoprophylaxis failure were 0%, 3.2% (3/95), 6.7% (19/282) and 7.6% (5/66), respectively (P < 0.001 for the trend). All failure infants were born to hepatitis B e antigen (HBeAg)-positive mothers. Multivariate logistic regression analysis identified maternal HBV DNA levels [odds ratio (OR) = 1.88, 95% confidence interval (CI): 1.07-3.30] and detectable HBV DNA in the cord blood (OR = 39.67, 95% CI: 14.22-110.64) as independent risk factors for immunoprophylaxis failure. All failure infants were born to HBeAg-positive mothers with HBV DNA levels >/= 6 log(10) copies/mL. The presence of HBV DNA in cord blood predicted failure to passive-active immunization.

BACKGROUND: High serum levels of lipopolysaccharide (LPS) with LPS-MD-2/TLR4 complex activated NF-kb and cytokine cause hepatic necrosis in animal models. We investigated the dynamic changes of LPS levels in patients with acute on chronic hepatitis B liver failure (ACHBLF). METHODS: We enrolled ACHBLF patients for a 12-week study. Patients' LPS levels were measured along with 10 healthy controls. Patients on supportive care and recovered without intervention(s) were analyzed. Patients' LPS levels during the disease progression phase, peak phase, and remission phase were compared with healthy controls. RESULTS: Among 30 patients enrolled, 25 who received interventions or expired during the study period were excluded from the analysis, five patients on supportive care who completed the study were analyzed. Significant abnormal distributions of LPS levels were observed in patients in different phases (0.0168+/-0.0101 in progression phase; 0.0960+/-0.0680 in peak phase; 0.0249+/-0.0365 in remission phase; and 0.0201+/-0.0146 in controls; respectively, p<0.05). The highest level of LPS was in the peak phase and significantly elevated when compared to controls (0.0201+/-0.0146 vs. 0.0960+/-0.0680, p = 0.007). There were no statistically significant differences in LPS levels between healthy controls and subjects in the progression phase or remission phase. Dynamic changes of LPS were correlated with MELD-Na in the progression phase (p = 0.01, R = 0.876) and in the peak phase (p = 0.000, R = -1.00). CONCLUSIONS: Significant abnormal distributions of LPS levels were observed in ACHBLF with the highest level in the peak phase. The dynamic changes of LPS were correlated with disease severity and suggested LPS causing secondary hepatic injury.