Evidence for Use of Tenofovir in Pregnancy to Prevent Perinatal Transmission of Hepatitis B Infection.

Perinatal transmission of hepatitis B virus continues to be a serious global public health concern. Transmission failures are related to high maternal viremia. Several antiviral therapies reduce maternal viremia around the time of delivery and decrease maternal-to-child-transmission. This chapter is a review of current studies that, ultimately, have provided strong evidence for the efficacy and safety of 3 antiviral drugs in pregnancy-lamivudine, telbivudine and tenofovir. The latter drug is the particular focus of this chapter which will show that tenofovir is the preferred antiviral therapy in pregnant women because of its potency, safety profile, and low risk of resistance.

[Consensus on clinical management of hepatitis B virus- infected women of childbearing age].

The mother-to-child transmission(MTCT) of hepatitis B virus (HBV) is the dominant cause of chronic HBV infection. In order to achieve the goal of "zero" MTCT before pregnancy, during pregnancy, and after pregnancy; standardized management for hepatitis HBV infection in women of childbearing age should be regulated. The content of this consensus includes: screening and treatment of HBV in pregnant women and women of childbearing age, treatment of hepatitis B during pregnancy, preventive measures and evaluation of combined immunization of hepatitis B immunoglobulin and hepatitis B vaccine in newborns, anti-viral therapy for all pregnant women with a high HBV DNA level and post-partum period related management. In addition, 16 recommendations were formed for clinicians to standardize the clinical management of HBV infection in women of child-bearing age.

Hepatitis B in Pregnancy.

Chronic hepatitis B virus (HBV) infection is estimated to affect >350 million people worldwide and represents a significant cause of morbidity and mortality related to cirrhosis and hepatocellular carcinoma. Mother-to-child transmission (MTCT) of HBV remains an important source of incident cases of HBV. Current barriers to eradication of incident HBV infections via MTCT include underutilization of immunoprophylaxis with hepatitis B vaccination and hepatitis B immune globulin in certain endemic regions as well as failure of immunoprophylaxis.

Effects of hepatitis B surface antigen (HBsAg) positivity of donors in HBsAg(+) renal transplant recipients: comparison of outcomes with HBsAg(+) and HBsAg(-) donors.

AIM: The aim of this study was to determine the effects of hepatitis B surface antigen (HBsAg) positivity of the donors on graft survival and liver complications in HBsAg(+) renal transplant recipients. PATIENTS AND METHOD: A group of 55 patients who underwent renal transplantation (RTx) in our hospital between 2001 and 2012 were included in the study. Patients were divided into 2 groups. Group 1 (n = 50) consisted of HBsAg(+) renal transplant recipients (RTR) whose donors were HBsAg(-). In Group 2 (n = 5), RTR and donors were both HBsAg(+). Lymphocyte cross matches, number of mismatches, donor types, renal replacement treatment modalities, drugs of induction treatment, and preoperative hepatitis B virus DNA titers of the groups were similar. In Group 1, 42 patients were taking lamivudine, 3 patients were taking entecavir, and 5 patients were taking tenofovir. All of the patients in Group 2 were taking lamivudine. Patient and graft survival rates, graft functions, acute hepatitis rates, acute rejection rates, and other clinical outcomes of the groups were compared. RESULTS: Demographic data of the groups were similar. Acute rejection rates (P = 0.458), graft survival rates (P = 0.515), and patient survival rates (P = 0.803) were also similar. No significant difference was found between the groups in terms of acute hepatitis rate (P = 0.511), glomerular filtration rate (calculated by Modification of Diet in Renal Disease formula) in the last follow-up (P = 0.988), alanine aminotransferase levels (P = 0.069), or delayed graft function rate (P = 0.973). Rates of chronic allograft dysfunction and new onset diabetes mellitus after transplantation were similar. CONCLUSION: Our study revealed that, RTx from HBsAg(+) donors to HBsAg(+) recipients is safe with antiviral treatment.

Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

Mother-to-child transmission of HBV: review of current clinical management and prevention strategies.

Mother-to-child transmission (MTCT) of HBV is responsible for approximately half of the HBV transmission routes and continues to be a challenging problem worldwide. Even after the development of effective vaccines and clear World Health Organization guidelines toward HBV several decades ago, 1-9% newborns of HBV-carrying mothers still acquire HBV in early life as a result of in utero infection. The prevention of MTCT is of high importance, because chronically infected individuals function as a reserve for sustained HBV transmission, and 25% of them can develop asymptomatic liver cirrhosis and hepatocellular carcinoma. In this article, we review the canonical and novel HBV infection routes/mechanisms, influencing factors, diagnostic criteria, and interruption strategies for HBV MTCT. The preventative strategy of HBV MTCT has evolved from routine postpartum HB immune globulin (HBIG) plus HB vaccine schedules to administration of HBIG or nucleoside analogs during pregnancy and minimizing the exposure of maternal body fluids to the newborn during delivery.

[Risk Management of HBV Reactivation: Construction of Check System].

In recent years, reactivation of HBV in patients receiving cancer chemotherapy or immunosuppressive therapy has been a problem. Generally, HBV-DNA levels are elevated prior to HBsAg concentration, and then hepatic dysfunction is observed in the process of hepatitis by HBV reactivation. Therefore, the monitoring of HBV-DNA is useful for the prediction of hepatic dysfunction, and nucleoside/nucleoside analogue (NA) administration is able to prevent this HBV reactivation. According to these facts, "Guidelines for the Prevention of HBV Reactivation in Patients Receiving Immunosuppressive Therapy or Chemotherapy", 2009 (revised as "JSH Guidelines for the Management of Hepatitis B Virus Infection", 2013) is established, and the diagnostic algorithm of HBsAg, anti-HBc, anti-HBs, and HBV-DNA has relevant descriptions. Combination therapy with rituximab and steroid for malignant lymphoma has a high risk of leading to fulminant hepatitis and, consequently, the guidelines are widely followed in such cases. We introduced the improvement of electronic medical recording and ordering systems in collaboration with hepatologists, and such a system has been widely used. Although the monitoring of HBV-DNA levels is required every 1-3 months, the guidelines are not followed strictly in cases such as rheumatoid disease and solid tumors only with chemotherapy or steroid treatment. Since a DNA assay is complicated and expensive, cost-effective, time-saving, and highly sensitive/specific measurements are required as well. Therefore, Lumipulse HBsAg-HQ (CLIA method) with high sensitivity is expected to be used for the monitoring of HBV reactivation.

The impact of HBV or HCV infection in a cohort of HIV-infected pregnant women receiving a nevirapine-based antiretroviral regimen in Malawi.

BACKGROUND: Coinfection with the hepatitis viruses is common in the HIV population in sub-Saharan Africa. The aim of this study was to assess, in a cohort of HIV-infected pregnant women receiving antiretroviral drugs (ARVs), the prevalence of HBV and HCV infections and to determine the impact of these infections on the occurrence of liver toxicity and on the viro-immunological response. METHODS: Women were screened for HBsAg and HCV-RNA before starting, at week 25 of gestational age, an antiretroviral regimen consisting of lamivudine and nevirapine plus either stavudine or zidovudine. Women with CD4+ < 350/mm3 continued ARVs indefinitely, while the other women interrupted treatment 6 months postpartum (end of breastfeeding period). Both groups were followed for 2 years after delivery. Liver function was monitored by alanine aminotransferase (ALT) measurement. The Cox proportional hazards model was used to identify factors associated with the emergence of liver toxicity. RESULTS: A total of 28 women out of the 309 enrolled in the study (9.1%) were coinfected with HBV (n. 27), or HCV (n. 1). During follow-up 125 women (40.4%) developed a grade ≥ 1 ALT elevation, 28 (9.1%) a grade ≥ 2 and 6 (1.9%) an elevation defining grade 3 toxicity. In a multivariate model including age, baseline CD4+ count and hemoglobin level, the presence of either HBV or HCV infection was significantly associated with the development of an ALT increase of any grade (P = 0.035). Moderate or severe liver laboratory toxicity (grade ≥ 2) was more frequent among women with baseline CD4+ > 250/mm3 (P = 0.030). In HBV-infected women a baseline HBV-DNA level above 10,000 IU/ml was significantly associated to the development of liver toxicity of grade ≥ 1 (P = 0.040). Coinfections had no impact on the immunological and virological response to antiretroviral drugs up to 2 years after delivery. CONCLUSIONS: In this cohort of nevirapine-treated women the presence of HBV or HCV was associated only to the development of mild liver toxicity, while the occurrence of moderate or severe hepatoxicity was correlated to a baseline CD4+ count > 250/mm3. No statistically significant effect of the coinfections was observed on the efficacy of antiretroviral therapy.

Hepatitis B virus reactivation in a juvenile rheumatoid arthritis patient under treatment and its successful management: a complicated case.

Juvenile rheumatoid arthritis is a common chronic inflammatory disease in the childhood and it can differentiate rarely into spondiloarthropaties. It is one of the important causes of chronic pain and disability. Some of the drugs used for the treatment have immunosupressive activity. One of the serious side-effects of immunosupressive treatment is activation of opportunistic pathogens. Hepatitis B virus (HBV) is one of these pathogens, and the rate of carriers in the population is considerably high. It can cause liver damage and death if reactivated. Thus, the management of oppotunistic pathogens becomes a complex issue when treating rheumatic diseases with immunosupressive drugs. In this case report, we present a juvenile rheumatoid arthritis patient whose liver enzymes raised while he was under treatment and afterwards HBV reactivation was determined as the cause. When reactivation was detected, we started controlled antiviral therapy. We achieved successful clinical and laboratory results after adding biological agents to the treatment. Careful evaluation of the patients who have indication for immunosuppressive agents and regular follow-up in case of infection may be protective from severe morbidity and/or mortality.

Nucleoside analogue therapy following one-year course of hepatitis B immunoglobulin in preventing hepatitis B virus reactivation after living donor liver transplantation.

The combination therapy with hepatitis B immunoglobulin (HBIG) and nucleoside analogue is well tolerated for the hepatitis B recipients after liver transplantation, but its cost is an important problem in these days. Here we report the efficacy of nucleoside analogue therapy following one-year course of HBIG plus nucleoside analogue after living donor liver transplantation (LDLT). Out of 103 LDLTs, we selected 14 recipients who received the post-transplant therapy against reactivation of hepatitis B virus for more than 30 months. Those were eight patients with chronic hepatitis B, three with fulminant hepatitis, and three whose donors were positive for antibody to HB core antigen (HBc). During two days after the operation, HBIG (40,000 units) was administered, and the serum level of antibody to HB surface antigen (HBs) was maintained at around 150 IU/L for one year by monthly administration of HBIG. After one year, HBIG was withdrawn. A nucleoside analogue was administered daily from just after LDLT, and it was continued up to the present. Among the 14 patients, two recipients had recurrence of hepatitis B. Three patients, including one patient with recurrence of hepatitis B, died due to hepatocellular carcinoma or its associated cirrhosis; namely, their deaths are unrelated to hepatitis B-related diseases. The remaining 11 patients are leading normal lives. In conclusion, nucleoside analogue therapy after one-year course of HBIG plus nucleoside analogue is feasible and cost-effective in preventing HBV reactivation. But the patients are still at risk of breakthrough and some patients may need continued prophylaxis with HBIG.

Guides concerning tenofovir exposure via breastfeeding: A comparison of drug dosages by developmental stage.

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir, and after being administered orally, it converts to tenofovir in the blood. With the increasing use of TDF in women for treatment and prevention of mother-to-child transmission (MTCT) of both human immunodeficiency virus (HIV) and hepatitis B virus (HBV), or the pre-exposure prophylaxis (PrEP) for HIV, many nursing mothers have to understand the risk of exposure to tenofovir via breastmilk and make the decision about breastfeeding while on TDF treatment. Despite the safety record of TDF in pregnancy, some guidelines recommend against its use during breastfeeding. In this paper, we compared the dosage levels of tenofovir exposure in fetuses, breastfed infants, and children receiving tenofovir treatment. We found that breastfed infants were exposed to only 0.5%-16% of the tenofovir dosage that fetuses experienced via placental transfer, and 0.01-0.04% of the recommended weight-adjusted therapeutic dose. The assessment of toxicity risk from the dose perspective is an important and natural way of addressing safety concerns about exposure to tenofovir via breastfeeding. Based on the safety data from fetuses and children with tenofovir exposure, and the comparatively negligible exposure dosage from breastfeeding, our study supports mothers on TDF treatment should be encouraged to breastfeed.

Corticosteroid improves liver function but does not curb the clinical progression of hepatitis B virus-related acute-on-chronic pre-liver failure.

Background: Hepatitis B virus-related acute-on-chronic pre liver failure (HBV pre-ACLF) has the potential for progression to HBV ACLF. Whether corticosteroid is useful for HBV pre-ACLF remains heterogeneous. This study aimed to evaluate the efficacy of short-term (5 days) and low-dose dexamethasone (5mg/d) toward HBV pre-ACLF.Design and methods: One hundred twenty-one patients with HBV pre-ACLF were randomly divided into two groups: medical comprehensive treatment (MCT) group and corticosteroid treatment (CT) group. Laboratory measurements at admission and 7 days post-admission were compared between the two groups, respectively. Hospitalization periods and clinical progression were also monitored and compared between the two groups.Results: Higher than normal levels of ALT, AST, TBIL, DBIL, TBA and GLO were observed at 7 days after admission in patients in the MCT group than in CT group (p < 0.001).Patients in the CT group had shorter inpatient days than the MCT group (p = 0.002).During hospitalization and treatment, the incidence of HBV ACLF was not substantially different between the two groups (14.8% vs. 8.3%, p = 0.271).Conclusions: Corticosteroid is effective at improving the liver function and decreasing hospitalization periods of patients with HBV pre-ACLF but does not prevent HBV pre-ACLF from progressing to HBVACLF.

Hepatitis B core-related antigen assay is useful for monitoring the antiviral effects of nucleoside analogue therapy.

OBJECTIVE: The clinical significance of the hepatitis B virus core-related antigen (HBcrAg) assay in monitoring the antiviral effects of lamivudine is reviewed. METHODS: The HBcrAg assay simultaneously measured serum levels of hepatitis B core (HBc) and e (HBe) antigens using monoclonal antibodies which recognize common epitopes of these two denatured antigens. RESULTS: Although serum HBcrAg levels correlated linearly with those of hepatitis B virus (HBV) DNA in natural course, the decrease in HBcrAg was significantly slower than in HBV DNA after initiation of lamivudine administration. We analyzed the clinical significance of HBV DNA and HBcrAg levels to predict the occurrence of lamivudine resistance. HBV DNA measurement may be useful to identify patients who are at high risk of developing lamivudine resistance, and HBcrAg measurement may help to detect patients who are at low risk of drug resistance. The measurement of HBcrAg was also found to be a useful prognosticator for reactivation of hepatitis after cessation of lamivudine administration. CONCLUSION: The HBcrAg assay is indeed useful for monitoring the antiviral effects of lamivudine, and we propose that it be adopted as a serum marker which reflects the amount of HBV covalently closed circular DNA in hepatocytes.

Hepatitis B virus-related vasculitis manifesting as severe peripheral neuropathy following influenza vaccination.

We report the case of a 68-year-old man who developed hepatitis B virus (HBV)-related vasculitis, manifesting as mononeuritis multiplex, 8 days after influenza vaccination. The patient was a carrier of wild-type HBV, and had never received influenza vaccination. Histologic examination of the left sural nerve revealed necrotising vasculitis predominantly involving small blood vessels. HbsAg deposits were observed at a high density around the epineurial blood vessels of the sural nerve. He was treated with prednisone and Lamivudine. His condition improved gradually. However, seroconversion of HBs and HBe Ag was not detected. At the last follow-up 2 years later, his vascilitis did not recur. On the basis of the time of onset of vasculitis, the presumptive immune-mediated pathology of this disorder suggests a possible etiologic link with influenza vaccine. To our knowledge, our case is the first to show vasculitis of peripheral nerves proven pathologically after influenza vaccination.