Journal of Contaminant Hydrology 75 (2004) 281 – 296 Quantifying the effects of fumarate on in situ reductive dechlorination rates Kimberly J. Hagemana,*, Jennifer A. Fieldb, Jonathan D. Istokc, Lewis Semprinic aDepartment of Chemistry, Oregon State University, 1007 Agriculture and Life Sciences, Corvallis, OR 97331-7301, United States bDepartment of Environmental and Molecular Toxicology, Oregon State University,
Hbv treatment and pregnancy
HBV treatment and pregnancy Jörg Petersen⇑ Liver Unit, IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg Hamburg, Germany See Article, pages MS The management of hepatitis B virus (HBV) infection in preg- often results in clinical remission This scenario is in contrast nancy is complex. Because infection with HBV in infancy often to the oral antiviral agents that generally require long-term ther- leads to chronic disease, prevention of perinatal or vertical trans- apy and result in lower rates of stable HBeAg seroconversion and mission is a major goal. Worldwide, vertical transmission some HBsAg loss only in HBeAg positive patients For those remains the most frequent route of infection, particularly in who require therapy, it is advisable to discuss the issue of preg- endemic areas where up to 20% of women of childbearing age nancy before starting the treatment.
may have HBV. These women constitute a reservoir for perinatal No antiviral agent has been approved for use in pregnancy.
transmission, which is associated with a very high rate of chro- Thus, when a woman on HBV antiviral therapy becomes preg- nicity . Without immunoprophylaxis, up to 90% of infants nant, a decision needs to be made whether she should continue born to hepatitis B e antigen (HBeAg)-positive mothers become therapy for the duration of the pregnancy or if therapy should HBV chronically infected. However, the maternal screening pro- be withdrawn immediately. As with all decisions during preg- grams and universal vaccination in newborns with active and nancy, the health of the mother and the fetus must be considered passive immunoprophylaxis have dramatically reduced HBV independently. From the perspective of the fetus, the major con- transmission rates. But even with the use of appropriate prophy- cern is the risk of exposure to medication during early embryo- laxis with HBV immunoglobulin (HBIG) and HBV vaccination, a genesis. From the perspective of the mother, the major issue is signiﬁcant risk of vertical transmission remains, particularly in whether stopping or switching medication will adversely affect mothers with high viral loads and positive hepatitis B e antigen both short- and long-term liver disease outcomes. In general, if (HBeAg) status. In one series of mothers with high viral loads, this the mother is known to have signiﬁcant ﬁbrosis, therapy should risk was as high as 28% . An HBV DNA level greater than be continued because the risk of ﬂare with withdrawal of therapy 107 copies/ml is an important risk factor for HBV transmission could result in reactivation and even decompensation of her liver Wiseman et al. recently studied 298 chronically HBV- disease. This effect on the mother's health could also impact the infected women and their infants, who were vaccinated and health of the fetus.
who received HBIG. The infants were tested for HBV at 9 months Decisions about initiating therapy during pregnancy again of age and showed an HBV rate of 8.5% born to mothers with must include consideration of the risks and beneﬁts for the virus levels greater than 8 log10 copies/ml. There is no indication mother and the fetus; furthermore, in which trimester the ther- to perform a caesarian section to reduce HBV transmission if vac- apy should be started must be considered, too. Interferon has cination and HBIG are administered accordingly.
antiproliferative actions and is contraindicated during pregnancy.
Factors that inﬂuence treatment choices in women of child- Furthermore, all polymerase inhibitors interfere with the replica- bearing age include safety in pregnancy and breastfeeding, efﬁ- tion of mitochondrial DNA, and this can result in mitochondrial cacy of the agent, its barrier to resistance, length of therapy, toxicity leading to the lactic acidosis syndrome Although and most important, the cause of treatment, i.e. treating the lactic acidosis syndrome is very uncommon in adults, less is mother because of an advanced liver disease or treating the known about the potential ramiﬁcations of mitochondrial toxic- unborn child to prevent transmission.
ity in the developing fetus. These effects may be more diverse, If pregnancy is contemplated in near future, it may be prudent because toxicity may affect organogenesis.
to delay therapy until after the child is born. This approach Of the nucleoside and nucleotide analogs indicated for the requires a careful assessment of the degree of hepatic activity treatment of chronic HBV infection, all are classiﬁed as Food and ﬁbrosis. Although it is not to be used in the pregnant woman, and Drug Administration (FDA) pregnancy risk category C except interferon can be used in the woman of childbearing age, because for tenofovir and telbivudine, which are category B. Most human therapy with this agent is for a deﬁned period of 48 weeks and experience with antiviral drug therapy in pregnancy has beenwith lamivudine. More than 4600 women have been exposed tothe drug during their second or third trimester and reported ⇑ Address: IFI Institute for Interdisciplinary Medicine, Asklepios Klinik St. Georg to the Antiretroviral Pregnancy Registry (APR). The APR monitors Hamburg, Lohmuhlenstrasse 5, D-20099 Hamburg, Germany. Tel.: + 49 40 the safety of antiretroviral agents in the United States of pregnant 181885 3796; fax: + 49 40 181885 3788.
E-mail address: women who have been exposed to lamivudine, tenofovir, Journal of Hepatology 2011 vol. xxx j xxx–xxx
emtricitabine, or other antiviral drugs. Despite the large number number of pregnant HBsAg positive women. The disadvantages of enrolled patients and reassuring results showing no signiﬁcant are the short follow up, only seven months after delivery, and increase in birth defects, there are limitations, including short fol- the lack of results of virologic breakthrough and resistance data.
low-up and recording only defects identiﬁed at birth. Develop- Furthermore, it is not a randomized study, patients were allo- mental anomalies (e.g. cardiac or neurologic defects) identiﬁed cated depending on their own wishes and prophylaxis was at a later date may therefore be omitted. Similar registries spon- started either during the second trimester or during the third tri- sored by the pharmaceutical industry have been severely limited mester but without a deﬁnitive time point. It is unclear whether by poor enrollment and provide little meaningful data. For the mothers with high levels of viremia started earlier compared to APR, no signiﬁcant difference was reported in the rate of adverse those with low levels of viremia. The risk of HBV transmission outcomes if the initial exposure of any HBV drug was in the ﬁrst could have been analyzed even better in relation to the time of trimester (2.7%) compared to the second or third trimester (2.5%) starting prophylaxis in addition to HBV DNA levels. The primary of pregnancy or compared to a non HIV nontreated general end point of the study was deﬁned as undetectable HBsAg and HBV DNA at birth and at month 7. This is a short period of fol- Even though lamivudine is classiﬁed as FDA pregnancy risk cat- low-up to analyze HBV perinatal transmission, at least newborns egory C, it is associated with the risk of birth defects that is not should be followed for 1 year. Nevertheless, this study is adding higher than the baseline birth defect rate. A meta-analysis of 10 very important information to our very limited knowledge of randomized clinical trials (RCTs) examining 951 HBV carrier moth- safety of polymerase inhibitors in pregnant women and helps ers was reported to evaluate the efﬁcacy of lamivudine in reducing to support the ‘‘B'' rating of telbivudine.
in utero transmission of HBV . The RCTs evaluated included Rather than switching agents, withdrawal of treatment for the newborns who received immunoprophylaxis at birth and women duration of pregnancy may be preferable in some cases, espe- who were treated with lamivudine from 24 to 32 weeks of gesta- cially to the mother who wants to avoid any potential future risk tion, until delivery to 1 month post-delivery. Newborns in the lam- to the fetus. What would be the consequence to the mother of ivudine group had a 13–24% signiﬁcantly lower incidence of stopping treatment completely? The natural history of chronic intrauterine exposure and a lower perinatal infection rate at 9– HBV in pregnancy has not been well described. Limited data exist 12 months. This report was limited by the quality of the studies to suggest that, rarely, severe complications of HBV occur late in included. On the other hand, in a recent poster presented at EASL pregnancy, with reports of liver failure in previously asymptom- 2011 in Berlin Ayres et al. showed that although the therapy atic individuals . Data speciﬁcally addressing the risk of stop- with lamivudine achieved an HBV DNA load reduction of ping therapy during pregnancy are only anecdotal.
3 log10 IU/ml, in 20% of the pregnant women, the viral load Overall, it appears that the risk of an adverse outcome with remained high (>1 107 IU/ml) and resistant mutations were continuing antiviral therapy during pregnancy is likely to be very detectable only after three months of therapy, calling for more low. However, therapy could be discontinued with close observa- potent antiviral drugs to be used to prevent transmission.
tion of the mother to avoid continued fetal exposure during the Of the two agents classiﬁed as FDA pregnancy risk category B, ﬁrst trimester, especially in the patient who does not have only tenofovir received this classiﬁcation based on the data col- advanced ﬁbrosis.
lected in human exposure, so far. There have been no other pub- When deciding on starting therapy in the third trimester, the lished studies using entecavir, adefovir, or emtricitabine for perinatal transmission outcome of prior pregnancies should be preventing HBV vertical transmission, and these drugs should considered. If previous pregnancies did not result in perinatal be switched immediately, if a woman becomes pregnant.
transmission, then a viral load of greater than 107 copies/ml The experience with tenofovir in pregnant women consists of should be used to determine if therapy should be initiated (sim- 606 women in their ﬁrst trimester and 336 in their second trimes- ilar to women who had no children). However, if perinatal trans- ter from the APR. The rate of birth defects associated with tenofovir mission did occur with a prior pregnancy, then the risk of ranges from 1.5% (second-trimester use) to 2.3% (ﬁrst-trimester perinatal transmission in the current pregnancy is likely higher.
use), which is again similar to the background rate. Telbivudine In such cases, strong consideration for initiating therapy in the received its pregnancy risk category B rating based on animal stud- third trimester is recommended, regardless of the mother's viral ies; there were few human pregnancy registry data up to now.
load at the end of the second trimester.
In this issue of the Journal of Hepatology, Han et al. present a Despite the position from the American Academy of Pediatrics prospective study that evaluates the efﬁcacy of telbivudine stating that breastfeeding is not contraindicated in naïve women for preventing HBV newborn infection performed in 230 preg- with HBV if HBIG and vaccination have been administered nant HBsAg positive patients with HBV DNA levels of accordingly for mothers on antiviral therapy, breastfeeding >1.0 106 copies/ml. The study shows that telbivudine plus vac- cannot be recommended. According to prescribing information, cination is superior to HBIG and HBV vaccines only in newborns it has not been recommended that women breastfeed their to prevent HBV transmission (0% vs. 8%). This study reconﬁrms infants while taking lamivudine or tenofovir, to avoid risking data from a recent study of 31 pregnant women in China, treated postnatal transmission of HIV-1 infection (package inserts lami- with telbivudine started at weeks 28–32 of pregnancy and con- vudine and tenofovir). Although it is known that lamivudine tinued to 30 days postpartum All babies received active and tenofovir are both excreted into human breast milk, little is and passive immunoprophylaxis. The infection rate was 0% in known about the extent of exposure of antiviral agents during those treated with telbivudine and 13.3% in the untreated breastfeeding. Thus, little is known about the overall safety of breastfeeding in this setting.
The advantages of the study by Han et al. are the use of tel- In summary, treatment of HBV infection during pregnancy bivudine, a more potent antiviral drug than lamivudine with a remains a challenge, the risks and beneﬁts must be weighed care- lower risk of HBV drug resistance and the inclusion of a large fully and there are still numerous gaps in our knowledge. The Journal of Hepatology 2011 vol. xxx j xxx–xxx
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Journal of Hepatology 2011 vol. xxx j xxx–xxx
Diabetes & Metabolism (Paris) 2000, 26, 337-351 POSTPRANDIAL REACTIVE HYPOGLYCEMIA J.F. BRUN, C. FEDOU, J. MERCIER SUMMARY - Postprandial reactive hypoglycemia (PRH) can be di- ´ SUME´ - Hypoglycémie réactionnelle post-prandiale. agnosed if sympathetic and neuroglucopenic symptoms develop concur- Le diagnostic d'hypoglycémie réactionnelle (HR) nécessite l'observation