Calvin Q. Pan

Virologic factors associated with failure to passive-active immunoprophylaxis in infants born to HBsAg-positive mothers.

Summary.  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 log10 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 log10 copies/mL. The presence of HBV DNA in cord blood predicted failure to passive–active immunization.

An Algorithm for Risk Assessment and Intervention of Mother to Child Transmission of Hepatitis B Virus

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.

Tenofovir to Prevent Hepatitis B Transmission in Mothers with High Viral Load

BACKGROUND Few data are available regarding the use of tenofovir disoproxil fumarate (TDF) during pregnancy for the prevention of mother-to-child transmission of hepatitis B virus (HBV). METHODS In this trial, we included 200 mothers who were positive for hepatitis B e antigen (HBeAg) and who had an HBV DNA level higher than 200,000 IU per milliliter. Participants were randomly assigned, in a 1:1 ratio, to receive usual care without antiviral therapy or to receive TDF (at an oral dose of 300 mg per day) from 30 to 32 weeks of gestation until postpartum week 4; the participants were followed until postpartum week 28. All the infants received immunoprophylaxis. The primary outcomes were the rates of mother-to-child transmission and birth defects. The secondary outcomes were the safety of TDF, the percentage of mothers with an HBV DNA level of less than 200,000 IU per milliliter at delivery, and loss or seroconversion of HBeAg or hepatitis B surface antigen at postpartum week 28. RESULTS At delivery, 68% of the mothers in the TDF group (66 of 97 women), as compared with 2% in the control group (2 of 100), had an HBV DNA level of less than 200,000 IU per milliliter (P<0.001). At postpartum week 28, the rate of mother-to-child transmission was significantly lower in the TDF group than in the control group, both in the intention-to-treat analysis (with transmission of virus to 5% of the infants [5 of 97] vs. 18% [18 of 100], P=0.007) and the per-protocol analysis (with transmission of virus to 0 vs. 7% [6 of 88], P=0.01). The maternal and infant safety profiles were similar in the TDF group and the control group, including birth-defect rates (2% [2 of 95 infants] and 1% [1 of 88], respectively; P=1.00), although more mothers in the TDF group had an increase in the creatine kinase level. After the discontinuation of TDF, alanine aminotransferase elevations above the normal range occurred more frequently in mothers in the TDF group than in those in the control group (45% [44 of 97 women] vs. 30% [30 of 100], P=0.03). The maternal HBV serologic outcomes did not differ significantly between the groups. CONCLUSIONS In a cohort of HBeAg-positive mothers with an HBV DNA level of more than 200,000 IU per milliliter during the third trimester, the rate of mother-to-child transmission was lower among those who received TDF therapy than among those who received usual care without antiviral therapy. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01488526.).

Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

BACKGROUND The novel prodrug tenofovir alafenamide delivers the nucleotide reverse transcriptase inhibitor tenofovir to target cells more efficiently at a lower dose than tenofovir disoproxil fumarate, thereby reducing systemic exposure. We compared the efficacy and safety of the two drugs in patients with HBeAg-negative chronic hepatitis B virus (HBV) infection in a non-inferiority study. METHODS In this ongoing randomised, double-blind, phase 3, non-inferiority study in 105 centres in 17 countries, patients with HBeAg-negative chronic HBV were randomly assigned (2:1) by a computer-generated allocation sequence (block size six), stratified by plasma HBV DNA concentration and previous treatment status, to receive once-daily oral doses of tenofovir alafenamide 25 mg or tenofovir disoproxil fumarate 300 mg, each with matching placebo. Participants, investigators, and those assessing outcomes were masked to group assignment. Eligible patients were aged at least 18 years with HBeAg-negative chronic HBV infection (with plasma HBV DNA concentrations of >20 000 IU/mL), serum alanine aminotransferase concentrations of greater than 60 U/L in men or greater than 38 U/L in women and at no more than ten times the upper limit of normal, and estimated creatinine clearance of at least 50 mL/min (by the Cockcroft-Gault method). The primary efficacy endpoint was the proportion of patients who had HBV DNA less than 29 IU/mL at week 48 in those who received at least one dose of study drug; the study was powered to show non-inferiority with a 10% efficacy margin of tenofovir alafenamide compared with tenofovir disoproxil fumarate. Bone and renal safety, and key secondary safety endpoints were assessed sequentially. The study will be conducted for a total of 3 years as a double-blind comparison to assess the longer term response to treatment. This study is registered with ClinicalTrials.gov, number NCT01940341. FINDINGS Between Sept 12, 2013, and Oct 31, 2014, 426 patients were randomly assigned (285 assigned to tenofovir alafenamide and 141 assigned to tenofovir disoproxil fumarate; one patient assigned to tenofovir disoproxil fumarate did not receive the treatment. 268 (94%) of 285 patients receiving tenofovir alafenamide had HBV DNA less than 29 IU/mL at week 48 versus 130 (93%) of 140 patients receiving tenofovir disoproxil fumarate (difference 1·8% [95% CI -3·6 to 7·2]; p=0·47), which demonstrates non-inferiority. Patients receiving tenofovir alafenamide had significantly smaller mean percentage declines in bone mineral density than those receiving tenofovir disoproxil fumarate (hip -0·29% [95% CI -0·55 to -0·03] vs -2·16% [-2·53 to -1·79], adjusted percentage difference 1·87% [95% CI 1·42 to 2·32; p<0·0001]; spine -0·88% [-1·22 to -0·54] vs -2·51% [-3·09 to -1·94], adjusted percentage difference 1·64% [95% CI 1·01 to 2·27]; p<0·0001). At week 48, mean change in serum creatinine was small in both groups (tenofovir alafenamide 0·01 mg/dL [95% CI 0·00 to 0·02] vs tenofovir disoproxil fumarate 0·02 mg/dL [0·00 to 0·04], adjusted percentage difference -0·01 mg/dL [95% CI -0·03 to 0·01]; p=0·32), but patients receiving tenofovir alafenamide had a smaller reduction in creatinine clearance (median change in estimated glomerular filtration rate -1·8 mL/min [IQR -7·8 to 6·0] vs -4·8 mL/min [-12·0 to 3·0]; p=0·004). Most adverse events were mild to moderate in severity in the two treatment groups. The most common adverse events overall were headache (tenofovir alafenamide 40 [14%] patients vs tenofovir disoproxil fumarate 14 [10%] patients), nasopharyngitis (30 [11%] vs 15 [11%]), and upper respiratory tract infection (35 [12%] vs ten [7%]). 14 (5%) patients receiving tenofovir alafenamide and nine (6%) patients receiving tenofovir disoproxil fumarate had serious adverse events, none of which was deemed by investigators to be related to study treatment; one patient in the tenofovir disoproxil fumarate group died, but this was not deemed to be related to study treatment. INTERPRETATION In patients with HBeAg-negative chronic HBV, the efficacy of tenofovir alafenamide was non-inferior to that of tenofovir disoproxil fumarate, and had improved bone and renal effects. Longer term follow-up is needed to better understand the clinical impact of these changes. FUNDING Gilead Sciences.

Barriers to Screening for Hepatitis B Virus Infection in Asian Americans

BackgroundRoutine screening for hepatitis B virus (HBV) infection can identify individuals who need vaccination or treatment, as vaccination can prevent HBV infection. Although the overall prevalence of HBV infection in the United States is low (<1%), it is high (~10%) in Asian Americans. However, HBV screening rates in this population have been reported to be low.AimsThis article systemically reviews the reported prevalence of HBV infection, the rate of HBV screening and access to HBV care, barriers for HBV screening and care, and a possible approach for improving HBV screening in Asian Americans.MethodsArticles published from 1999 to 2011 on HBV screening and disparity in Asian Americans were identified by searching electronic databases (PubMed and Cochrane Library), and reviewed.ResultsPublished studies, including a recent report from the Institute of Medicine of the National Academies, revealed HBV screening rates are low in Asian Americans. This review addresses the need for HBV screening in Asian Americans. Barriers to HBV screening are related to patients, providers, and/or the healthcare system. Screening programs that incorporate culturally sensitive interventions and include educational outreach, vaccination, and a link to healthcare services improve rates of HBV screening and vaccination in this at-risk community.ConclusionsA strategy that integrates efforts from the healthcare profession, federal agencies, and the community will be needed to improve HBV screening and access to HBV care for Asian Americans.

Risk of vertical transmission of hepatitis B after amniocentesis in HBs antigen-positive mothers

BACKGROUND & AIMS Despite appropriate immunoprophylaxis, HBV vertical transmission (VT) occurs in 5-10% of infants born to HBs-antigen (HBsAg)+ mothers. We investigated whether amniocentesis increases the risk of transmission. METHODS We performed a case-control study on infants who were born to HBsAg+ mothers without antiviral exposure and completed appropriate immunization. Infants born to mothers with amniocentesis were compared to those without amniocentesis to assess VT rates, which were defined by the percentage of infants with HBsAg positivity when they were 7-12 months old. RESULTS Of the 642 consecutive infants enrolled, 63 infants with amniocentesis were compared with 198 matched infants selected from the remaining 579 infants without amniocentesis. There was a higher VT rate in infants with amniocentesis than in those without amniocentesis (6.35% vs. 2.53%; p=0.226). Maternal HBV DNA levels before amniocentesis were further stratified to <500 copies/ml, 500-6.99 log10 copies/ml, and ⩾ 7 log10 copies/ml for subset analyses. There were no significant differences in the VT rates between the amniocentesis group and the control group if the maternal HBV DNA levels were <6.99 log10 copies/ml. However, a significantly higher VT rate was observed in the amniocentesis group vs. the control group if the maternal HBV DNA levels were ⩾ 7 log10 copies/ml (50% vs. 4.5%, respectively, p=0.006). According to baseline value risk analyses, performing amniocentesis on highly viremic mothers was a risk factor for HBV transmission (OR=21.3, 95% CI: 2.960-153.775). CONCLUSIONS Amniocentesis performed on HBsAg+ mothers with HBV DNA ⩾ 7 log10 copies/ml significantly increased the frequency of VT. HBsAg+ women who plan to have amniocentesis should be evaluated for the risk of VT and stratified according to their HBV DNA levels. Further prospective studies are warranted to verify our findings.

Antiviral Therapy for Chronic Hepatitis B in Pregnancy

The management of chronic hepatitis B (CHB) during pregnancy remains a challenge and involves various aspects of maternal-fetal care. Despite the standard immunoprophylaxis, a significant portion of infants born to highly viremic mothers remain infected with hepatitis B virus (HBV). Emerging data suggest that antiviral therapy in the third trimester can prevent immunoprophylaxis failure. To minimize fetal exposure to antiviral agents, antiviral therapy during pregnancy should be reserved for mothers with advanced disease or who are at risk for hepatic decompensation. Current safety data suggest that lamivudine, telbivudine, or tenofovir may be used during pregnancy. However, the timing in initiating antiviral therapy requires careful assessment of risks and benefit. The authors provide a systematic review of the features of HBV during pregnancy, risk factors for vertical transmission, and evidence-based data on antiviral use during pregnancy. They propose an algorithm to assess the need of antiviral treatment and monitor mothers with CHB.

Randomized phase II study of GS-4774 as a therapeutic vaccine in virally suppressed patients with chronic hepatitis B

BACKGROUND & AIMS GS-4774 is a heat-inactivated, yeast-based, T-cell vaccine designed to elicit hepatitis B virus (HBV)-specific T-cell responses. We evaluated the safety, tolerability and efficacy of GS-4774 in patients with chronic HBV infection. METHODS In this phase II study, 178 patients with chronic HBV infection and no cirrhosis who were virally suppressed on an oral antiviral (OAV) for ⩾1year were randomized (1:2:2:2) to continue OAV alone or receive OAV plus GS-4774 2, 10, or 40 yeast units (YU) subcutaneously every 4weeks until week 20. OAV was continued for the remainder of the study. Efficacy was measured by decline in serum hepatitis B surface antigen (HBsAg) from baseline to week 24. RESULTS Baseline characteristics were similar across groups (mean age, 45-50years; male, 62-74%; Asian, 68-80%; hepatitis B e antigen (HBeAg)-positive, 24-26%; mean HBsAg, 2.5-3.1log10IU/ml). There were no significant differences between groups in mean HBsAg declines from baseline to week 24 or 48. Five HBeAg-positive patients receiving GS-4774 experienced HBeAg loss vs. none in the control group. Three GS-4774 40 YU-treated patients had HBsAg declines ⩾0.5log10IU/ml, but no patient experienced loss of serum HBsAg. No virologic breakthrough occurred. Injection site reactions were the most frequent adverse event (AE), and there were no treatment discontinuations. CONCLUSIONS GS-4774 was well tolerated, but did not provide significant reductions in serum HBsAg in virally suppressed patients with chronic hepatitis B. Efficacy of GS-4774 in treatment-naïve patients remains to be determined. LAY SUMMARY GS-4774 is a therapeutic vaccine designed to improve the immune response against hepatitis B virus (HBV) in patients who already have chronic infection with HBV. In this study, GS-4774 was safe and well tolerated in patients with chronic HBV infection receiving oral antiviral therapy, but did not result in a clinical benefit. Combination approaches with other agents, and evaluation in other populations of patients with HBV are ongoing to determine if GS-4774 might have a therapeutic benefit. CLINICAL TRIAL REGISTRATION NUMBER NCT01943799.

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

Summary.  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 log10 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) log10 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) log10 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) log10 and 0.43 (−0.09–1.13) log10 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.

Hepatitis Outreach Network: A practical strategy for hepatitis screening with linkage to care in foreign-born communities

BACKGROUND & AIMS Many foreign-born persons in the US are at high risk of chronic hepatitis B (HBV) and C (HCV) infections, yet are not aware of their infection, and lack healthcare coverage or linkage to care. METHODS A unique partnership, the Hepatitis Outreach Network, combines the expertise and resources of the Mount Sinai School of Medicine, the NYC Department of Health and Mental Hygiene, and community-based organizations, to provide education, screening and link to care in communities with high prevalence of chronic viral hepatitis. Comprehensive HBV and HCV screening identifies infected patients, who then receive further evaluation from either local or Mount Sinai physicians, combined with patient-navigators who organize follow-up visits. RESULTS Of 1603 persons screened, 76 had HBV and 75 had HCV. Importantly, screening for HCV based on traditional risk factors would have missed 67% of those who tested positive. Of the 76 persons with HCV infection, 49 (64%) received a medical evaluation (26 with local providers and 23 at Mount Sinai). Of the 49 HCV-infected persons evaluated, treatment was recommended in 11 and begun in 8 (73%). Of the 76 persons with HBV infection, 43 (57%) received a medical evaluation (31 with local providers and 12 at Mount Sinai). Of the 43 HBV-infected persons evaluated, treatment was recommended and begun in 5 (100%). CONCLUSIONS Hepatitis Outreach Network has successfully established novel proof of concept for identifying HBV and HCV infections in foreign-born persons through use of several unique elements that effectively link them to care.