Hepatitis B reactivation after kidney transplantation in hepatitis B surface antigen‐negative,core antibody‐positive recipients

Nowadays, intensive immunosuppressive therapy including rituximab is commonly used prior to kidney transplantation (KT), raising concerns over hepatitis B virus (HBV) reactivation among hepatitis B surface antigen (HBsAg)‐negative and anti‐hepatitis B core (HBc)‐positive KT recipients. Recent practice guidelines suggested watchful monitoring or antiviral prophylaxis for the first 6‐12 months, the period of maximal immunosuppression. However, the actual risk for HBV reactivation, and whether short‐term antiviral therapy in the early period is necessary, remains unclear. A total of 449 HBsAg‐negative and anti‐HBc‐positive KT recipients were analysed for HBV reactivation. During a median follow‐up of 6.7 (interquartile range: 4.2‐9.4) years, HBV reactivation was observed in 9 patients (2.0%). The median time of HBV reactivation from KT was 2.8 years (range: 1.4‐11.5 years), with cumulative incidence rates of 0%, 1% and 2% for 1, 3 and 5 years, respectively. There were no severe adverse outcomes, including liver transplantation or mortality related to HBV reactivation. The risk of HBV reactivation was not high, even in anti‐HBs‐negative patients (n = 60, 4% at 5 years), ABO mismatch (n = 92, 4% at 5 years), use of rituximab (n = 66, 3% at 5 years) or plasmapheresis (n = 17, 7% at 5 years), and acute rejection (n = 169, 3% at 5 years). In conclusion, the HBV reactivation risk was not high and the time of detection was not clustered in the early post‐KT period. Our findings favour continued watchful monitoring over antiviral prophylaxis in the early period.     

Predictors of sustained functional cure in hepatitis B envelope antigen‐negative patients achieving hepatitis B surface antigen seroclearance with interferon‐alpha–based therapy

Hepatitis B surface antigen (HBsAg) loss is considered a functional cure in chronic hepatitis B (CHB). However, the durability of HBsAg loss after stopping treatment remains unknown. This study aimed to assess the sustained functional cure achieved by interferon therapy in hepatitis B envelope antigen (HBeAg)‐negative CHB patients. In this prospective study, 176 HBeAg‐negative CHB patients with functional cure were enrolled for 12 weeks of cessation treatment, and treatment information and baseline data were collected. Hepatitis B virus (HBV) biomarkers and clinical biochemical indicators were evaluated every 3 months; liver imaging examinations were performed every 3‐6 months during the 48‐week follow‐up. The sustained functional cure was evaluated. After the 48‐week follow‐up, the sustained functional cure rate was 86.63%. The cumulative rates of HBsAg reversion and HBV DNA reversion were 12.79% and 2.33%, respectively. Consolidation treatment ≥ 12 weeks after HBsAg loss achieved a significantly higher rate of sustained functional cure and significantly lower rate of HBsAg reversion than consolidation treatment < 12 weeks (76.19% vs 90.00%, P = 0.022 and 23.81% vs 9.23%, P = 0.014, respectively). Patients with hepatitis B surface antibody (HBsAb) had higher rate of sustained functional cure than patients achieving HBsAg loss but without HBsAb (89.86% vs 73.53%, P = 0.012). Consolidation treatment ≥ 12 weeks (odds ratio [OR] 16.478; 95% confidence interval [CI], 2.135‐127.151; P = 0.007) and high HBsAb levels (OR 8.312; 95% CI, 1.824‐37.881; P = 0.006) were independent predictors of sustained functional cure. Results suggested that 12 weeks of consolidation therapy after HBsAg clearance and elevated HBsAb levels help to improve functional cure.     

Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg‐negative and anti‐HBc antibodies‐positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer

Summary. We studied clinical outcome and clinico‐virological factors associated with hepatitis B virus reactivation (HBV‐R) following cancer treatment in hepatitis B virus surface antigen (HBsAg)‐negative/anti‐hepatitis B core antibodies (anti‐HBcAb)‐positive patients. Between 11/2003 and 12/2005, HBV‐R occurred in 7/84 HBsAg‐negative/anti‐HBcAb‐positive patients treated for haematological or solid cancer. Virological factors including HBV genotype, core promoter, precore, and HBsAg genotypic and amino acid (aa) patterns were studied. Patients presenting with reactivation were men, had an hepatitis B virus surface antibody (HBsAb) titre <100 IU/L and underwent >1 line of chemotherapy (CT) significantly more frequently than controls. All were treated for haematological cancer, 3/7 received haematopoietic stem cell transplantation (HSCT), and 4/7 received rituximab. Using multivariate analysis, receiving >1 line of CT was an independent risk factor for HBV‐R. Fatal outcome occurred in 3/7 patients (despite lamivudine therapy in two), whereas 2/4 survivors had an HBsAg seroconversion. HBV‐R involved non‐A HBV genotypes and core promoter and/or precore HBV mutants in all cases. Mutations known to impair HBsAg antigenicity were detected in HBV DNA from all seven patients. HBV DNA could be retrospectively detected in two patients prior cancer treatment and despite HBsAg negativity. HBV‐R is a concern in HBsAg‐negative/anti‐HBcAb‐positive patients undergoing cancer therapy, especially in males presenting with haematological cancer, a low anti‐HBsAb titre and more than one chemotherapeutic agent. HBV DNA testing is mandatory to improve diagnosis and management of HBV‐R in these patients. The role of specific therapies such as rituximab or HSCT as well as of HBV aa variability deserves further studies.     

Low incidence of hepatitis B virus reactivation during chemotherapy among diffuse large B‐cell lymphoma patients who are HBsAg‐negative/ HBcAb‐positive: a multicenter retrospective study

Background: Reactivation of hepatitis B virus (HBV) is less common in lymphoma patients with prior resolved HBV infection [characterized by hepatitis B surface antigen (HBsAg)‐negative/hepatitis B core antibody (HBcAb)‐positive status] compared with chronic HBV infection (HBsAg positive) when receiving chemotherapy alone. The use of rituximab in chemotherapy regimen might increase the risk of HBV reactivation in patients with prior resolved HBV infection. However, the incidence of HBV reactivation is uncertain, and prophylactic antiviral treatment for this group of patients during rituximab‐containing chemotherapy is controversial. The objective of this study was to determine the incidence of HBV reactivation in HBsAg‐negative/HBcAb‐positive patients diagnosed of diffuse large B‐cell lymphoma (DLBCL) and treated with CHOP‐like or RCHOP‐like regimen. In addition, this study also aims to explore the relationship of HBV reactivation and HBV serology. Methods: Patients were identified using data from six university hospitals collected between January 1998 and November 2008. Four hundred and thirty‐seven patients with complete data were selected based on the diagnosis of CD20+ DLBCL, availability of HBV serum markers prior to initiation of chemotherapy and during the development of hepatitis, completion of at least four cycles of chemotherapy using CHOP‐like or RCHOP‐like regimen, and follow‐up for at least 6 months after completion of treatment. The characteristics of the HBsAg‐negative/HBcAb‐positive patients treated with CHOP‐like regimen were compared to those treated with RCHOP‐like regimen. Results: Eighty‐eight patients of the total 437 patients had pretreatment serology of prior resolved hepatitis B, with a prevalence of 20.1%. Among them, 45 patients received CHOP‐like regimen while 43 patients received RCHOP‐like regimen. Five patients developed hepatitis during treatment, two from CHOP group and three from RCHOP group. Only one patient treated with RCHOP had hepatitis associated with HBV reactivation, while the other four patients did not have evidence of HBV reactivation. Those four patients also demonstrated positive HBsAb at baseline, while the only patient who suffered from HBV reactivation had negative HBsAb status. This patient was successfully treated with antiviral medications. There were no statistically significant risk factors predictive of HBV reactivation. Conclusions: The present study revealed a low HBV reactivation rate of 2.3% in prior resolved hepatitis B among DLBCL patients undergoing RCHOP‐like therapy.     

Antiviral prophylaxis for hepatitis B carriers improves the prognosis of diffuse large B‐cell lymphoma in Taiwan – a population‐based study

The prevention of hepatitis B virus (HBV) reactivation during rituximab treatment for diffuse large B‐cell lymphoma (DLBCL) is important in the HBV‐endemic area. This population‐based study examines the impact of antiviral prophylaxis for DLBCL patients with HBV infections. We identified 3702 adult patients with newly diagnosed DLBCL between 2011 and 2015 receiving R‐CHOP, R‐CVP, CHOP or CVP from the Taiwan Cancer Registry. We further stratified them into three groups: HBsAg‐negative patients (HBV‐negative, N = 2921), HBV carriers who received antiviral prophylaxis (HBV + Px, N = 711), and HBV carriers who did not receive antiviral prophylaxis (HBV + No Px, N = 70). HBV + Px patients were the youngest, and 69·4% received entecavir for antiviral prophylaxis. The median overall survival (mOS) of HBV‐negative and HBV + Px patients was similar (74·23 months and not reached, respectively). However, the mOS of HBV + No Px patients was only 35·61 months (P = 0·0028 compared with HBV + Px patients), indicating that antiviral prophylaxis improves OS in HBsAg‐positive DLBCL patients. The multivariate analysis showed that the HBV status and antiviral prophylaxis was an independent prognostic factor. In conclusion, our population‐based study illustrates the importance of antiviral prophylaxis in HBsAg‐positive DLBCL patients. Under antiviral prophylaxis, the survival of DLBCL patients with HBV infections was comparable to that of HBV‐negative patients.     

Loss of intrahepatic HBsAg expression predicts sustained response to peginterferon and is reflected by pronounced serum HBsAg decline

There is a lack of knowledge regarding the effect of peginterferon (PEG‐IFN) on the expression of intrahepatic hepatitis B core and surface antigen (HBcAg and HBsAg) in chronic hepatitis B (CHB) and its relation with response to therapy. Fifty‐two HBeAg‐positive and 67 HBeAg‐negative CHB patients with paired liver biopsies taken at baseline and after 1 year of PEG‐IFN therapy were studied. After PEG‐IFN therapy, HBeAg‐negative patients showed a significant reduction in both intrahepatic HBcAg (P = 0.04) and HBsAg expression (P < 0.001). In contrast, a reduction in intrahepatic HBcAg expression was not observed in HBeAg‐positive patients, while a trend in reduction of intrahepatic HBsAg staining was found (P = 0.09). Post‐treatment, 7 (13%) HBeAg‐positive and 9 (14%) HBeAg‐negative patients had no expression of intrahepatic HBsAg. Patients without any intrahepatic HBsAg expression post‐treatment were more likely to achieve a combined response (HBeAg loss with hepatitis B virus (HBV) DNA <2000 IU/mL for HBeAg ‐positive and HBV DNA <2000 IU/mL and normal alanine aminotransferase for HBeAg‐negative CHB): 71% vs 5% for HBeAg‐positive (P < 0.001) and 60% vs 16% for HBeAg‐negative patients (P = 0.004), respectively. Moreover, a more profound decline of serum HBsAg was observed in patients with absence of intrahepatic HBsAg staining (3.1 vs 0.4 log IU/mL, P < 0.001 and 1.7 vs 0.4 log IU/mL, P = 0.005 for HBeAg‐positive and HBeAg‐negative CHB, respectively). In conclusion, PEG‐IFN reduces expression of intrahepatic HBsAg. Loss of HBsAg as assessed by immunohistochemistry from the liver predicts a sustained response and is reflected in a pronounced serum HBsAg decline.     

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 ≥2000 IU/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 <2000 IU/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 <2000 IU/mL before DAA therapy.     

Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy

With the increasing use of potent immunosuppressive therapy, reactivation of hepatitis B virus (HBV) in endemic regions is becoming a clinical problem requiring special attention. A recent annual nationwide survey clarified that HBV reactivation related to immunosuppressive therapy has been increasing in patients with malignant lymphoma, other hematological malignancies, oncological or rheumatological disease. In the survey, rituximab plus steroid‐containing chemotherapy was identified as a risk factor for HBV reactivation in hepatitis B surface antigen (HBsAg) negative patients with malignant lymphoma. In this setting, HBV reactivation resulted in fatal fulminant hepatitis regardless of the treatment of nucleoside analog. The Intractable Hepatobiliary Disease Study Group and the Study Group for the Standardization of Treatment of Viral Hepatitis Including Cirrhosis jointly developed guidelines for preventing HBV reactivation. The essential features of the guideline are as follows. All patients should be screened for HBsAg by a sensitive method before the start of immunosuppressive therapy. Second, hepatitis B core antigen (HBcAb) and hepatitis B surface antibody (HBsAb) testing should be performed in HBsAg negative patients, especially those receiving intensive immunosuppressive therapy. Prophylaxis with nucleoside analogs is essential for preventing HBV reactivation in HBsAg positive patients. In contrast, HBsAg negative with HBcAb and/or HBsAb positive patients should be monitored monthly for an increase in serum HBV DNA during and 12 months after completion of chemotherapy. Nucleoside analogs should be administrated immediately when HBV DNA becomes positive during this period. This strategy facilitates commencement of nucleoside analogs at an early stage of HBV reactivation and results in prevention of severe hepatitis.     

T‐ and B‐cell responses and previous exposure to hepatitis B virus in ‘anti‐HBc alone’ patients

A serologic response to hepatitis B virus (HBV) defined as ‘anti‐HBc alone’ is commonly observed, but its significance remains unclear. This study aimed to define the relationship between ‘anti‐HBc alone’ serostatus and HBV infection, including HBV‐specific T‐ and B‐cell memory responses. We enrolled 31 ‘anti‐HBc alone’ patients. Total HBV DNA and cccDNA were tested by nested polymerase chain reaction (PCR) analysis in liver samples from 22 ‘anti‐HBc alone’ patients vs controls (chronic or resolved HBV infection), followed by HBsAg/HBcAg immunohistochemical (IHC) staining. IFN‐γ secretion by HBV‐specific T cells was compared in individuals who were ‘anti‐HBc alone’ (n = 27), resolved HBV (n = 21), chronic HBV (n = 24) and 12 healthy controls using enzyme‐linked immunospot (ELISpot) assays. An HBsAg‐IgG B‐cell ELISpot assay was performed in ‘anti‐HBc alone’ patients before and after one dose of recombinant HBsAg vaccine. The majority (23/31, 74.2%) of the ‘anti‐HBc alone’ individuals were co‐infected with HCV. Infrequent intrahepatic total HBV DNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV‐specific T‐cell responses were similar between ‘anti‐HBc alone’ individuals and HBV resolvers. Circulating HBV‐memory B‐cell responses were detected in all ‘anti‐HBc alone’ individuals, consistent with an HBsAg‐specific memory pool. After one HBV vaccine dose, increased anti‐HBs antibody levels were observed, accompanied by an expansion of HBsAg‐specific memory B cells (P = 0.0226). ‘Anti‐HBc alone’ individuals showed HBV‐specific T‐cell and memory B‐cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection.     

Long‐term entecavir therapy results in falls in serum hepatitis B surface antigen levels and seroclearance in nucleos(t)ide‐naïve chronic hepatitis B patients

Entecavir (ETV) is reported to result in suppression of hepatitis B virus DNA (HBV DNA) replication with minimal drug resistance. However, information on the long‐term effect of such therapy on serum hepatitis B surface antigen (HBsAg) level and elimination of HBsAg is not available. ETV therapy was started in 553 nucleos(t)ide‐naïve patients with chronic hepatitis B infection (HBeAg positive: 45%) in our hospital. Serum HBsAg levels were measured serially by the Architect assay. The median baseline HBsAg was 2180 IU/mL (0.12–243 000 IU/mL), and median follow‐up period was 3.0 years, with 529, 475, 355, 247 and 163 patients followed‐up for 1, 2, 3, 4 and 5 years, respectively. At year 5, the mean log HBsAg decline from baseline was −0.48 log IU/mL, and the cumulative HBsAg clearance rate was 3.5%. Multivariate analysis identified HBV DNA level at baseline (<3.0 log copies IU/mL, odd ratio = 10.2; 95% confidence interval = 1.87–55.5, P = 0.007) and HBsAg level (<500 IU/mL, odd ratio = 29.4; 95% confidence interval = 2.80–333, P = 0.005) as independent predictors of HBsAg seroclearance. These results indicate that although serum HBsAg level declines gradually during ETV therapy, HBsAg seroclearance remains a rare event.     

Hepatitis B virus pregenomic RNA status can reveal the long‐term prognoses of chronic hepatitis B patients treated with nucleos(t)ide analogues

We examined whether the hepatitis B virus (HBV) pregenomic RNA (pgRNA) status after nucleos(t)ide (NA) treatment can predict the long‐time prognoses of chronic hepatitis B patients. Patients with chronic hepatitis B (98) who were treatment‐naïve and had begun a 7‐year NA therapy regimen were enrolled in this study. Biochemical indicators and serological markers of HBV infection were performed during therapy. HBV pgRNA was quantified by real‐time quantitative PCR with specific primers. During treatment, HBV DNA undetectable rates increased. The aminotransferase (ALT) normalization (ALT < 50 IU/L) and HBeAg‐negative rates also increased. After 48 weeks’ NA treatment, 48.28% (28/58) of HBV DNA undetectable patients still had HBV pgRNA‐positive. After 7 years of treatment, more HBV pgRNA‐negative patients (n = 35) achieved HBeAg clearance than the patients who were HBV pgRNA‐positive (n = 63) (19/23 vs 19/56, P < .00). HBV pgRNA‐positive patients also had an increased risk of failing to achieve HBeAg clearance (OR = 9.25, 95% CI: 2.75‐31.08). The median time to HBeAg clearance in the HBV pgRNA‐positive patients was longer than that of the HBV pgRNA‐negative patients (152 weeks vs 72 weeks). The HBV pgRNA‐positive patients also required more time to achieve HBV DNA undetectable (124 weeks, 95% CI: 103.33‐144.67 vs 48 weeks, 95% CI: 34.80‐61.20). The HBV pgRNA status after NA treatment can predict the long‐term prognoses of patients with chronic HBV. Patients who remain HBV pgRNA‐positive after 48 weeks of NA treatment have an increased risk of not achieving HBeAg clearance, need more time to achieve HBeAg clearance and undetectable HBV DNA load.     

Meta‐analysis: Association between hepatitis B virus preS mutation and hepatocellular carcinoma risk

Previous observational studies suggested that hepatitis B virus (HBV) preS mutation plays an important role in the existence of HBV‐related hepatocellular carcinoma (HCC). However, the results are still debatable. With an increasing number of studies about this topic, this study employed a meta‐analysis to identify the association between HBV preS mutation and HCC risk. We searched for eligible studies from PubMed, ProQuest, CINAHL, ScienceDirect and Springer databases to assess the association between HBV mutation and HCC risk. This meta‐analysis was conducted using RevMan 5.3 to provide pooled estimate for odds ratio (ORs) with 95% confidence intervals (95% CIs). Twenty‐one clinical studies were included in this meta‐analysis study which consisted of 1738 participants with HBV‐related HCC and 3740 HBsAg‐positive patients without HCC. All studies used samples of Asian population. PreS deletion was the most common mutation found in all studies. We found that ORs of HBV overall preS deletion was associated with HCC (OR = 3.28; 95% CI = 2.32‐4.65; P < .00001; random‐effects model). Each preS1 and preS2 deletion was associated with increased risk of HCC, with OR 2.42 (95% CI = 1.25‐4.68, P = .008) and 3.36 (95% CI = 2.04‐5.55, P < .00001), respectively. PreS2 start codon mutation was also significantly associated with HCC risk (OR = 2.47; 95% CI: 1.15‐5.27; P = .02; random‐effect model). The result of this meta‐analysis suggested that HBV preS deletion (all, preS1 and preS2) and preS2 start codon mutation might contribute to the increased risk of HBV‐related HCC.     

Frequent delayed spontaneous seroclearance of hepatitis B virus after incident HBV infection among adult high‐risk groups

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)‐positive for > 6 months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985‐2002) who had anti‐hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan‐Meier curves. A total of 147 incident HBV infections occurred during follow‐up. On initial HBsAg testing after infection (6‐12 months), 42 (29%) were HBsAg‐positive and 105 (71%) were HBsAg‐negative (‘standard HBsAg seroclearance’). Of the 42 initially HBsAg‐positive individuals, 22 subsequently tested HBsAg‐negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg‐negative and HBV DNA‐negative (‘delayed HBsAg seroclearance’), while 27 remained HBsAg and/or HBV DNA‐positive (‘chronic HBV’). The 5‐year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg‐positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)‐co‐infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at‐risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct‐acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co‐infected MSM/PWUD are warranted prior to treatment initiation.     

Hepatitis B reactivation during cancer chemotherapy: an international survey of the membership of the American Association for the Study of Liver Diseases

Hepatitis B virus reactivation (HBVr) can be a serious complication of cancer chemotherapy. However, underutilization of HBV screening and secondary underutilization of antiviral prophylaxis have been frequently reported. The authors electronically distributed a 30‐point questionnaire to members of the American Association for the Study of Liver Diseases to capture experiences with HBVr during cancer chemotherapy. The questionnaire specified diagnostic criteria and collected information on HBV screening, antiviral prophylaxis and clinical outcomes. Ninety‐nine respondents reported 188 patients who met the criteria for HBV reactivation. Forty‐one practised outside the United States, and most were hepatologists (n = 71) or gastroenterologists (n = 12). One hundred and twenty‐six patients had haematologic malignancies, of which 88 (70%) had lymphoma. Seventy‐five patients (40%) had screening for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti‐HBc), and an additional 24 patients (13%) had HBsAg screening alone. Prophylactic antiviral therapy was reported in only 18 patients (10%). Chemotherapy was interrupted in 52 patients (41%) with haematologic malignancies and 26 of 41 patients (63%) with solid tumours (P = 0.01). Rituximab‐treated patients (n = 66) required hospitalization more frequently (P = 0.04), but their overall survival did not differ from individuals not treated with rituximab. Death due to liver failure was reported in 43 patients overall (23%). Underutilization of prophylactic antiviral therapy occured in a substantial number of patients who were found to be HBV infected prior to the initiation of cancer chemotherapy. The reasons for this need further exploration because reactivation results in serious yet preventable outcomes.     

Direct‐acting antivirals and hepatitis B virus (HBV) reactivation in co‐infected HBV/HCV kidney‐transplant recipients

Direct‐acting agents (DAAs) are highly efficient at treating hepatitis C virus (HCV) infections after kidney transplantation. Although drug agencies have recently warned of the risk of hepatitis B virus (HBV) reactivation after patients have received DAAs, reports have discrepant results in HBsAg‐positive and HBsAg‐negative patients. We report on 3 cases of HBV reactivation that were detected after achieving a DAA‐associated sustained virological response in 3 kidney‐transplant recipients initially HBsAg‐negative. In the first case, retrospective virological analysis revealed that HBsAgs had become positive and HBV DNA was detectable before initiating DAA therapy. In the second and third cases, HBV reactivation occurred 2 months and more than 1 year after stopping anti‐HCV therapy. These cases underline the discrepancies and highlight the need for comprehensive information before making definitive conclusions regarding the causal link between DAAs and HBV reactivation.     

Maternal hepatitis B surface antigen status and incidence of pre‐eclampsia

The relationship between chronic hepatitis B virus (HBV) infection with atherosclerosis and cardiovascular disorders remains unclear, and the impact of maternal HBV infection on the development of pregnancy‐induced hypertension (PIH) and pre‐eclampsia (PE) is also controversial. This retrospective cohort study was conducted to examine the relationship between maternal hepatitis B surface antigen (HBsAg) status with PIH and PE in singleton pregnancies that delivered at 24 weeks of gestation and beyond. Among the 86 537 cases in the cohort, 10% were HBsAg positive, and overall 2.0% had PIH, of whom 56.3% developed PE. HBsAg‐positive women had higher weight and body mass index (BMI), but lower incidences of advanced age, nulliparity, PIH (1.6% vs 2.0%, P = 0.007) and PE (0.8% vs 1.1%, P = 0.005). On multiple logistic regression analysis adjusting for the effects of nulliparity, advanced age, high BMI, and underlying renal, cardiac and autoimmune diseases, HBsAg carriage was associated with significantly reduced incidence of PIH (aOR 0.79, 95% CI 0.66–0.95) and PE (aOR 0.71, 95% CI 0.56–0.91). Our results indicate that maternal HBsAg carriage is independently associated with reduced PE. As chronic HBV infection alters the immune response of the individual, our observation could be related to enhanced maternal immunotolerance of the foetus and hence a reduction in the incidence of PE. The implications of our findings on the long‐term health outcome of the infected women, from cardiovascular morbidity to malignancies, warrant further studies.     

Hepatitis D virus infection,cirrhosis and hepatocellular carcinoma in The Gambia

Hepatocellular carcinoma (HCC) incidence is high in The Gambia, and hepatitis B virus (HBV) infection is the main cause. People coinfected with HBV and hepatitis D virus (HDV) have an even greater risk of HCC and cirrhosis. Using a new HDV quantitative microarray antibody capture (Q‐MAC) assay, we evaluated the association between HDV infection and HCC or cirrhosis among participants in The Gambia Liver Cancer Study. In this case‐control study, cases had HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) had no clinical evidence of liver disease and normal serum alpha‐foetoprotein. Participants were previously tested for hepatitis B surface antigen (HBsAg); we tested HBsAg+ specimens by HDV Q‐MAC, western blot and RNA assays. We evaluated separate cut‐offs of the Q‐MAC assay for predicting anti‐HDV and RNA positivity. Q‐MAC correctly identified 29/29 subjects who were western blot‐positive (sensitivity = 100%, specificity = 99.4%) and 16/17 who were RNA‐positive (sensitivity = 94.1%, specificity = 100%). Compared to controls, cases more often had HBV monoinfection (HBsAg+/HDV RNA?; 54.1% vs 17.0%; odds ratio [OR] = 6.28; P < 0.001) or HBV‐HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) based on HDV antibody status and adjusted for covariates (demographics, alcohol, smoking, body mass index, anti‐HCV and aflatoxin B1 exposure) yielded consistent results for both HBV monoinfection (adjusted OR = 8.29; 95% confidence interval = 5.74‐11.98) and HBV‐HDV coinfection (adjusted OR = 30.66; 95% confidence interval = 6.97‐134.95). In this Gambian population, HDV Q‐MAC had high sensitivity and specificity for both anti‐HDV and HDV RNA. HDV infection contributed to the high risk of HCC in The Gambia.     

Efficacy of antepartum administration of hepatitis B immunoglobulin in preventing mother‐to‐child transmission of hepatitis B virus

The aim of this study was to investigate the efficacy of antepartum administration of three doses of hepatitis B immunoglobulin (HBIG) in interrupting mother‐to‐child transmission (MTCT) of hepatitis B virus (HBV). In this trial, a total of 728 HBeAg‐positive pregnant women with chronic HBV infection who had an HBV DNA level higher than 6log₁₀ copies/mL were enrolled. They were divided into three groups based on individual preference. Subjects in group A and group B received 200 IU (unit) HBIG and 400 IU (unit) HBIG intramuscularly once a month at the third, second and first month before delivery, respectively. Subjects in the control group (C) received no special treatment. All the infants received passive‐active immunoprophylaxis. The HBsAg‐positive rate of all infants at 7‐12 months of age was 5.1% (37/728). Specifically, the HBsAg‐positive rate of infants was comparable in all three groups (5.3% vs 5.1% vs 5%, P = 0.988). No significant difference was found in anti‐HBs levels between the infants aged 7‐12 months in the three groups (P = 0.469). HBV DNA levels of the umbilical cord blood in the HBV‐infected group were higher than those in the uninfected group (5.2 vs 3.4log₁₀ copies/mL, P < 0.001), and these with family history of HBV infection were also higher (45.9% vs 28.5%, P = 0.034). To conclude, administration of passive‐active immunoprophylaxis to infants contributed to effective prevention of the MTCT of HBV; extra antepartum administration of HBIG during pregnancy could not decrease the rate of MTCT or increase the anti‐HBs levels of infants born to HBsAg‐positive mothers with HBV DNA higher than 6log₁₀ copies/mL.     

Relevance of hepatitis B surface antigen levels in patients with chronic hepatitis B during 5 year of tenofovir treatment

The role of quantitative hepatitis B surface antigen (HBsAg) levels in patients receiving highly potent oral antiviral therapy is controversial, and here, we determined the HBsAg response in 121 chronic hepatitis B patients treated with tenofovir 300 mg daily. During tenofovir treatment, HBsAg decline of ≥1.0 log from baseline was seen in 16.1%, 16.3%, 18.4%, 34.6%, 36.4% and 11.8%, 15.2%, 14.8%, 28.6%, 20% at years 1, 2, 3, 4, 5 for HBeAg‐positive and HBeAg‐negative patients, respectively. Early decline in HBsAg levels at week 4 was predictive of subsequent significant HBsAg level decline. HBeAg seroconversion occurred in 29.9% of HBeAg‐positive patients. On multinomial logistic regression, HBsAg level decline from baseline at week 4 and week 12 or any time subsequently did not correlate with HBeAg seroconversion and HBV DNA level decline from baseline at week 4 and week 12 (OR = 3.704; 95% CI = 1.511–9.076; P = 0.006 and OR = 1.732; 95% CI = 1.032–2.867; P = 0.037, respectively) was significantly predictive of seroconversion. A small proportion of chronic HBV‐infected patients treated with tenofovir exhibit a significant (≥1.0 log) decline in HBsAg levels. Early decline in HBsAg levels at week 4 was predictive of subsequent and significant HBsAg level decline. The HBsAg decline did not correlate with HBeAg seroconversion in HBeAg‐positive patients. Reduction in HBV DNA levels at week 4 and 12 correlated with seroconversion.     

Influence of hepatitis B virus reactivation on the recurrence of HBV‐related hepatocellular carcinoma after curative resection in patients with low viral load

It is unclear whether the reactivation of hepatitis B virus (HBV) influences the prognosis of hepatocellular carcinoma (HCC) after resection in patients with chronic hepatitis B. The aim of this study was to identify the influence of HBV reactivation on the recurrence of hepatitis B‐related HCC after curative resection in patients with low viral load (HBV DNA <2000 IU/mL). We retrospectively analysed a total of 130 patients who underwent curative resection for HBV‐related early stage HCC (single nodule; <5 cm/two or three nodules; <3 cm) with pre‐operative HBV DNA levels <2000 IU/mL with serial HBV DNA tests. The predictive factors including HBV reactivation for the recurrence of HBV‐related HCC after curative resection were investigated. Fifty‐three patients (41%) had HBV reactivation after resection among 130 patients. HBV reactivation was observed in 22 of 53 patients with undetectable baseline HBV DNA and in 31 of 77 patients with detectable baseline HBV DNA. Cumulative recurrence rates after resection at 1, 2 and 3 years were 17.0%, 23.3% and 31.4%, respectively. The multivariable analysis demonstrated that the risk factors for the recurrence were the presence of microvascular invasion (hazard ratio (HR) 2.62, P = 0.003), multinodularity (HR 4.61, P = 0.005), HBV reactivation after resection (HR 2.03, P = 0.032) and HBeAg positivity (HR 2.06, P = 0.044). HBV reactivation after curative resection is associated with the recurrence of HBV‐related HCC in patients with low viral load.