http://aidsinfo.nih.

gov/guidelines/html/3/perinatal-guidelines/197/tenofovirdisoproxil-fumarate--viread--tdfRecommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
Tenofovir Disoproxil Fumarate (Viread, TDF)
(Last updated:3/28/2014; last reviewed:3/28/2014)

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Section Only PDF (200 KB) Full Guideline PDF (1.6 MB) Recommendations Only PDF (269 KB) Tables Only PDF (401 KB) Tenofovir disoproxil fumarate (hereafter, tenofovir) is classified as Food and Drug Administration Pregnancy Category B. Animal Carcinogenicity Studies Tenofovir is mutagenic in one of two in vitro assays and has no evidence of clastogenic activity. Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were carried out at 16 times (mice) and 5 times (rats) human exposure. In female mice, liver adenomas were increased at exposures 16 times that observed in humans at therapeutic doses. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose. Reproduction/Fertility Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus associated with tenofovir. There were also no effects on fertility, mating performance, or early embryonic development when tenofovir was administered to male rats (600 mg/kg/day; equivalent to 10 times the human dose based on body surface area) for 28 days before mating and to female rats for 15 days before mating through Day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats administered 600 mg/kg/day. A retrospective analysis of 7,275 women (1,199 receiving tenofovir-based combination antiretroviral therapy) demonstrated a slight reduction in pregnancy rates but the findings were limited by the observational nature of the data and additional studies are needed for confirmation.1 Teratogenicity/Developmental Toxicity Chronic exposure of fetal monkeys to tenofovir at high doses (i.e., exposure equivalent to 25 times the area under the curve achieved with therapeutic dosing in humans) resulted in lower fetal circulating insulin-like growth factor (IGF)-1, higher IGF binding protein-3 levels, and were associated with lower overall body weights. A slight reduction in fetal bone porosity was also observed. Effects on these parameters were observed within 2 months of maternal treatment. Significant changes in maternal monkey bone biomarkers were noted but were primarily limited to the treatment period and were reversible.2 In newborn macaques exposed to tenofovir at high dose over a prolonged period, similar changes have been noted, as well as osteomalacia, bone fracture, hypophosphatemia, and nephrotoxicity. These toxicities appear to be dose- and age-related and are reversible. In contrast, no detectable effects on growth have been seen with administration of tenofovir for shorter durations or at lower doses to newborn or infant macaques. 3,4 In the Antiretroviral Pregnancy Registry, sufficient numbers of first-trimester exposures to tenofovir in humans have been monitored to be able to detect at least a 2-fold increased risk of overall birth defects. No such increase in birth defects has been observed with tenofovir. Among cases of first-trimester tenofovir exposure reported to the Antiretroviral Pregnancy Registry, the prevalence of birth defects was 2.3% (31 of 1,370 births; 95% CI, 1.5% to 3.2%) compared with a 2.7% total prevalence in the U.S. population, based on CDC surveillance.5 In addition, no association was seen between tenofovir administration and birth defects in two large U.S. cohorts, PACT 219/219C (n = 2,202) and P1025 (n = 1,112). 6,7 Placental and Breast Milk Passage Intravenous administration of tenofovir to pregnant cynomolgus monkeys resulted in a fetal/maternal concentration of 17%, demonstrating that tenofovir does cross the placenta.8 In studies of pregnant women on chronic tenofovir dosing, the cord-to-

maternal-blood ratio ranged from 0.60 to 1.03, indicating high placental transfer.9-12 In studies of pregnant women receiving single-dose tenofovir (with and without emtricitabine) in labor, the drugs were well-tolerated and the median tenofovir cord to maternal-blood ratio at delivery ranged from 0.55 to 0.73. 13,14 In a study evaluating intracellular tenofovir levels in newborns, intracellular tenofovir concentrations were detected in the peripheral blood mononuclear cells from cord blood in all infants after a maternal single dose of 600 mg tenofovir disoproxil fumarate with 400 mg emtricitabine, but intracellular tenofovir diphosphate was detectable in only 2 (5.5%) of 36.15 Two studies of neonatal dosing of tenofovir disoproxil fumarate resulted in tenofovir and tenofovir diphosphate levels similar to those in adults following either a single neonatal dose of 13 mg/kg or a regimen of 6 mg/kg administered daily for 7 days.14,15 Sixteen breast milk samples were obtained from five women who received 600 mg of tenofovir at the start of labor followed by 300 mg daily for 7 days. Tenofovir levels in breast milk ranged from 5.8 to 16.3 ng/mL, and nursing infants received an estimated 0.03% of the proposed oral dose of tenofovir disoproxil fumarate for neonates. 16 Human Studies in Pregnancy A retrospective population pharmacokinetic (PK) study was performed on samples collected for therapeutic drug monitoring from 46 pregnant women and 156 non-pregnant women receiving combination regimens including tenofovir. 17 Pregnant women had a 39% higher apparent clearance compared with non-pregnant women, which decreased slightly but significantly with increasing age. In study P1026s, tenofovir PKs were evaluated in 19 pregnant women receiving tenofovir-based combination therapy at 30 to 36 weeks gestation and 6 to 12 weeks postpartum.9 The percentage of women with tenofovir area under the curve exceeding the target of 2 g*hour/mL (the 10th percentile in non-pregnant adults) was lower in the third trimester (74%, 14 of 19 women) than postpartum (86%, 12 of 14 women) (P = .02); however, trough levels were similar in the two groups. A study of 34 women receiving tenofovir plus emtricitabine in the third trimester and postpartum has recently been reported. 11 Although similar decreases in PK parameters were observed during pregnancy, they were not associated with virologic failure. At the present time, standard dosing during pregnancy continues to be recommended. A case series found tenofovir to be well tolerated in 76 pregnant women, with only 2 stopping therapy, 1 for rash and the oth er for nausea. All 78 infants were healthy with no signs of toxicity, and all were HIV uninfected. 18 A follow-up study of 20 of the tenofovir-exposed infants and 20 controls found no differences between the groups in renal function, including cystatin C levels, through age 2 years.19 A retrospective review of 16 pregnancy outcomes in 15 heavily antiretroviral- experienced women demonstrated that tenofovir was well tolerated by the women and associated with normal growth and development in the infants.20 In a cross-sectional study of 68 HIV-exposed uninfected infants who had in utero exposure to combination regimens with (N = 33) or without (N = 35) tenofovir, the incidence of low birth weight and length measurements (<10th percentile) was comparable in the 2 groups and evaluation of quantitative bone ultrasound and parameters of bone metabolism gave similar measures between groups.21 Among 382 pregnancies occurring in 302 women in Uganda and Zimbabwe participating in the DART trialapproximately two-thirds of whom received tenofovir through more than 90% of their pregnancies there were no differences noted in mortality, birth defects, or growth.22 The Pediatric HIV/AIDS Cohort Study from the United States reported on the association of tenofovir use during pregnancy with early growth parameters in 449 HIV-exposed but HIV-uninfected infants.23 Of 2,029 infants, 449 (21%) had in utero exposure to tenofovir. There was no difference at birth between those exposed to combination drug regimens with or without tenofovir in low birth weight, small-for-gestational-age, and newborn length-for-age and head circumference-for-age z-scores (LAZ and HCAZ, respectively). At age 1 year, infants exposed to combination regimens with tenofovir had a slight but significantly lower adjusted mean LAZ and HCAZ than those without tenofovir exposure (LAZ: -0.17 vs. -0.03,P = .04; HCAZ: 0.17 vs. 0.42, P = .02), but not lower weight-for-age z-score. However, there were no significant differences between those with and without tenofovir exposure at age 1 year when defining low LAZ or HCAZ as <-1.5 z-score. Thus, these slightly lower mean LAZ and HCAZ scores are of uncertain significance.

References
1. 2. Maskew M, Westreich D, Firnhaber C, Sanne I. Tenofovir use and pregnancy among women initiating HAART. AIDS. 2012;26(18):2393-2397. Available at http://www.ncbi.nlm.nih.gov/pubmed/22951630. Tarantal AF, Castillo A, Ekert JE, Bischofberger N, Martin RB. Fetal and maternal outcome after administration of tenofovir to gravid rhesus monkeys (Macaca mulatta). J Acquir Immune Defic Syndr.2002;29(3):207-220. Available at http://www.ncbi.nlm.nih.gov/pubmed/11873070. 3. Van Rompay KK, Durand-Gasselin L, Brignolo LL, et al. Chronic administration of tenofovir to rhesus macaques from infancy through adulthood and pregnancy: summary of pharmacokinetics and biological and virological

effects. Antimicrob Agents Chemother. 2008;52(9):3144-3160. Available at http://www.ncbi.nlm.nih.gov/pubmed/18573931. 4. Van Rompay KK, Brignolo LL, Meyer DJ, et al. Biological effects of short-term or prolonged administration of 9-[2(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. Antimicrob Agents

Chemother. 2004;48(5):1469-1487. Available at http://www.ncbi.nlm.nih.gov/pubmed/15105094.

5. 6. Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry international interim report for 1 Jan 198931 July 2013. 2013. Available at http://www.APRegistry.com. Accessed March 5, 2014. Brogly SB, Abzug MJ, Watts DH, et al. Birth defects among children born to human immunodeficiency virus-infected women: pediatric AIDS clinical trials protocols 219 and 219C. Pediatr Infect Dis J. 2010;29(8):721-727. Available at http://www.ncbi.nlm.nih.gov/pubmed/20539252. 7. 8. Knapp KM, Brogly SB, Muenz DG, et al. Prevalence of congenital anomalies in infants with in utero exposure to antiretrovirals. Pediatr Infect Dis J. 2012;31(2):164-170. Available at http://www.ncbi.nlm.nih.gov/pubmed/21983213. Tarantal AF, Marthas ML, Shaw JP, Cundy K, Bischofberger N. Administration of 9-[2-(R)(phosphonomethoxy)propyl]adenine (PMPA) to gravid and infant rhesus macaques (Macaca mulatta): safety and efficacy studies. J Acquir Immune Defic Syndr Hum Retrovirol. 1999;20(4):323-333. Available at http://www.ncbi.nlm.nih.gov/pubmed/10096575. 9. Burchett S, Best B, Mirochnick M, et al. Tenofovir pharmacokinetics during pregnancy, at delivery, and postpartum. Paper presented at: 14th Conference on Retroviruses and Opportunistic Infections; 2007; Los Angeles, CA. 10. Bonora S, de Requena DG, Chiesa E, et al. Transplacental passage of tenofovir and other ARVs at delivery. Paper presented at: 14th Conference on Retoviruses and Opportunistic Infections; 2007; Los Angeles, CA. 11. Colbers A, Taylor G, et al. A comparison of the pharmacokinetics of tenofovir during pregnancy and post-partum. Paper presented at: 13th International Workshop on Clinical Pharmacology of HIV Therapy; 2012; Barcelona, Spain. 12. Hirt D, Urien S, Ekouevi DK, et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates (ANRS 12109). Clin Pharmacol Ther. 2009;85(2):182-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/18987623. 13. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their infants. Antimicrob Agents Chemother . 2011;55(12):59145922. Available at http://www.ncbi.nlm.nih.gov/pubmed/21896911. 14. Nielsen-Saines K, al. e. Tenofovir disoproxil fumarate (TDF) pharmacokinetics (PK) with daily dosing in the first week of life (HPTN 057). Abstract no. TUAB0201. Paper presented at: 19th International AIDS Conference; 2012; Washington, DC. 15. Hirt D, Ekouevi DK, Pruvost A, et al. Plasma and intracellular tenofovir pharmacokinetics in the neonate (ANRS 12109 trial, step 2). Antimicrob Agents Chemother. 2011;55(6):2961-2967. Available at http://www.ncbi.nlm.nih.gov/pubmed/21464249. 16. Benaboud S, Pruvost A, Coffie PA, et al. Concentrations of tenofovir and emtricitabine in breast milk of HIV-1-infected women in Abidjan, Cote d'Ivoire, in the ANRS 12109 TEmAA Study, Step 2. Antimicrob Agents

Chemother. 2011;55(3):1315-1317. Available at http://www.ncbi.nlm.nih.gov/pubmed/21173182.

17. Benaboud S, Hirt D, Launay O, et al. Pregnancy-related effects on tenofovir pharmacokinetics: a population study with 186 women. Antimicrob Agents Chemother. 2012;56(2):857-862. Available at http://www.ncbi.nlm.nih.gov/pubmed/22123690. 18. Habert A, Linde R, Reittner A, al e. Safety and efficacy of tenofovir in pregnant women. 15th Conference on Retroviruses and Opportunistic Infections; February 3-6, 2008, 2008; Boston, MA. 19. Linde R, Konigs C, Rusicke E, Haberl A, Reitter A, Dreuz W. Tenofovir therapy during pregnancy does not affect renal function in HIV-exposed children. 17th Conference on Retoviruses and Opportunistic Infections; February 27-March 2, 2010, 2010; San Francisco, CA. 20. Nurutdinova D, Onen NF, Hayes E, Mondy K, Overton ET. Adverse effects of tenofovir use in HIV-infected pregnant women and their infants. Ann Pharmacother. 2008;42(11):1581-1585. Available at http://www.ncbi.nlm.nih.gov/pubmed/18957630. 21. Vigano A, Mora S, Giacomet V, et al. In utero exposure to tenofovir disoproxil fumarate does not impair growth and bone health in HIV-uninfected children born to HIV-infected mothers. Antivir Ther. 2011;16(8):1259-1266. Available at http://www.ncbi.nlm.nih.gov/pubmed/22155907. 22. Gibb DM, Kizito H, Russell EC, et al. Pregnancy and infant outcomes among HIV-infected women taking long-term ART with and without tenofovir in the DART trial. PLoS Med. 2012;9(5):e1001217. Available at http://www.ncbi.nlm.nih.gov/pubmed/22615543. 23. Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIVexposed uninfected infants. AIDS. 2012;26(9):1151-1159. Available at http://www.ncbi.nlm.nih.gov/pubmed/22382151.

Natalie H. Bzowej
Author information Copyright and License information This article has been cited by other articles in PMC.

Abstract
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Introduction
It is estimated that 350 million to 400 million individuals worldwide are chronically infected with the hepatitis B virus (HBV) [1]. In regions with high prevalence, infection is most commonly acquired through either perinatal or horizontal transmission [2, 3]. The risk of progression to chronic HBV infection is inversely proportional to the age at which the infection was acquired. Without immunoprophylaxis, up to 90% of infants born to hepatitis B e antigen (HBeAg)positive mothers become infected. In contrast, only 20% to 30% of children exposed between ages 1 and 5 years, and fewer than 5% of adults, become infected [46]. Thus, women of childbearing age with chronic HBV infection remain an important source for continued spread of the virus. This article addresses several issues pertinent to hepatitis B therapy in pregnancy. First, the woman of childbearing age who may require therapy for hepatitis B is discussed, with particular emphasis on the timing of therapy, choice of an agent, and the patients desire to have children in the future. Second, an approach is outlined for the woman who is newly diagnosed with hepatitis B early in pregnancy. In addition, whether therapy should be continued, switched, or stopped if an HBV-infected woman is on treatment and becomes pregnant is debated. Finally, the question of whether a pregnant woman should be treated in the third trimester to help prevent perinatal transmission is addressed in a proposed algorithm for the management of HBV in pregnancy. Go to:

Therapy for HBV in Women of Childbearing Age

Seven therapies are approved by the US Food and Drug Administration (FDA) for the treatment of hepatitis B, including interferon (both standard and pegylated), lamivudine, adefovir, entecavir, telbivudine, and tenofovir [3]. Factors that influence treatment choice in women of childbearing age include safety in pregnancy and breastfeeding, efficacy of the agent, its barrier to resistance, and proposed length of therapy. If pregnancy is contemplated in the near future, it may be prudent to delay therapy until after the child is born [7]. This approach requires a careful assessment of the degree of hepatic activity and fibrosis, with either liver biopsy or noninvasive methods. Although it is not used in the pregnant woman, interferon can be used in the woman of childbearing age, because therapy with this agent is for a defined period (48 weeks) and often results in clinical remission with HBeAg seroconversion [8]. This scenario is in contrast to the oral antiviral agents that generally require long-term therapy and result in much lower rates of HBeAg seroconversion [3, 7]. For those who require therapy, it is advisable to discuss the issue of pregnancy before starting treatment. A planned pregnancy is preferable and may influence the choice and timing of therapy, or potentially the timing of pregnancy. In addition, given the relative paucity of evidence for most recommendations, decisions about treatment during pregnancy can be made with the luxury of time for consideration of all relevant issues. Treatment with tenofovir is an ideal choice, given its efficacy, high barrier to resistance, and safety profile in pregnancy [9, 10]. Lamivudine, another agent that is considered safe in pregnancy, has a high chance of emergence of resistant virus with prolonged therapy and therefore is no longer a first-line agent in the nonpregnant patient [3, 7, 10]. Go to:

Newly Diagnosed Chronic HBV in Pregnancy

The pregnant woman who is newly diagnosed with HBV early in pregnancy should undergo an assessment of her infection. Decisions about initiating therapy in this setting must include consideration of the risks and benefits for the mother and the fetus. The risk-benefit equation also depends upon the trimester of the pregnancy. The major determinant of the need for HBV therapy for the mother is the stage of her liver disease (both hepatic activity and fibrosis) [7]. Treatment is generally recommended if the mother is at risk of serious liver disease. Most women of childbearing age are likely to have mild disease; therefore, treatment can usually be postponed until after delivery. Because many of these women are in the immune-tolerant phase of infection (high HBV DNA levels with normal alanine transaminase [ALT] and inactive liver biopsy), therapy is generally not needed and no indication exists to start therapy during the early stages of pregnancy [3, 7]. Go to:

Therapy for Hepatitis B in Early Pregnancy

No antiviral agent has been approved by the FDA for use in pregnancy. Thus, when a woman on HBV antiviral therapy becomes pregnant, a decision needs to be made whether she should continue therapy for the duration of the pregnancy or if therapy

should be withdrawn immediately. As with all decisions during pregnancy, the health of the mother and the fetus must be considered independently. From the perspective of the fetus, the major concern is the risk of exposure to medication during early embryogenesis. From the perspective of the mother, the major issue is whether stopping or changing medication will adversely affect both short- and long-term liver disease outcomes. In general, if the mother is known to have significant fibrosis, therapy should be continued because the risk of flare with withdrawal of therapy could result in decompensation of her liver disease. This effect on the mothers health could also impact the health of the fetus. All HBV antivirals are inhibitors of either nucleoside or nucleotide polymerases. Although these drugs preferentially target the RNA-dependent DNA polymerase of HBV, they also interfere with replication of mitochondrial DNA, and this can result in mitochondrial toxicity leading to the lactic acidosis syndrome [11]. Although lactic acidosis syndrome is very uncommon in adults, less is known about the potential ramifications of mitochondrial toxicity in the developing fetus. These effects may be more diverse, because toxicity may affect organogenesis. Safety data on HBV antivirals during pregnancy come from two major sources: the Antiretroviral Pregnancy Registry (APR) [10] and the Development of Antiretroviral Therapy Study (DART) [12]. The APR is an international, voluntary, prospective exposure registration cohort study of women exposed to antiretroviral therapies, most of whom are HIV-1 monoinfected. As of January 2010, data from 11,867 pregnancies were available. However, these data included only 112 women with HBV monoinfection, in whom birth defects were recorded in 2.7% of live births. This statistic compares favorably to the 2.72% rate reported by the Centers for Disease Control and Prevention (CDC) birth defect surveillance system. Table 1 shows the number of cases of early versus late exposure and the rate of birth defects for each of the FDA-approved HBV antivirals. No significant difference was reported in the rate of adverse outcomes if the initial exposure of any HBV drug was in the first trimester (2.7%) compared to the second or third trimester (2.5%) of pregnancy. Although these data are reassuring, it is important to look at the HBV agents specifically. Lamivudine and tenofovir are the two agents with the most in vivo experience in the first trimester and appear to be safe. For telbivudine and entecavir, only 5 and 12 pregnancies with exposure in the first trimester are recorded in the registry, with no adverse outcomes reported. Although the APR is extremely useful, it has limitations, including short follow-up and recording only defects identified at birth. Developmental anomalies (eg, cardiac or neurologic defects) identified at a later date may therefore be omitted.

Table 1 Antiretroviral pregnancy registry data The DART study is a 6-year, multicenter, randomized trial of antiretroviral therapy among adults with symptomatic HIV-1 infection or advanced disease/AIDS in Africa. The 3% rate of congenital anomalies reported in this study also compares favorably to the 2.72% reported by the CDC birth defect surveillance system [12]. Go to:

Continuing, Switching, or Discontinuing Therapy?

If the decision is made to continue HBV therapy during pregnancy, the question then becomes whether the drug should be replaced with an agent that has more in vivo experience during pregnancy (ie, is thought to be safer). For example, because safety data are lacking for entecavir, and because it is an FDA pregnancy class C drug (Table 2), switching to an alternate therapy should be strongly considered [13]. If desired, the original treatment could eventually be resumed after delivery. The two most commonly used agents in pregnancy are lamivudine and tenofovir. Lamivudine is also categorized as a class C agent by the FDA because of reports of toxicity in rabbits with first trimester exposure. However, because it was the first oral agent approved for the treatment of HBV, extensive clinical experience exists. The APR data also suggest that lamivudine is safe despite its pregnancy C classification. Although there is less clinical experience with tenofovir, it is categorized as a class B agent by the FDA and has the added benefit of a very high genetic barrier to resistance, with no reported resistance identified to date [13, 14]. However, telbivudine, another class B agent, is seldom used, for two reasons [13]. First, there is minimal in vivo experience in pregnancy, and second, telbivudine has a low barrier to resistance [15].

Table 2 Food and drug administration pregnancy categories Rather than switching agents, withdrawal of treatment for the duration of pregnancy may be preferable, especially to the mother who wants to avoid any potential future risk to the fetus. What would be the consequence to the mother of stopping treatment completely? The natural history of chronic HBV in pregnancy has not been well described. Limited data exist to suggest that, rarely, severe complications of HBV occur late in pregnancy, with reports of liver failure requiring liver transplantation in previously asymptomatic individuals [16]. Data specifically addressing the risk of stopping therapy during pregnancy are anecdotal. Our knowledge of those risks relating to cessation of therapy is derived from early clinical trials in nonpregnant patients, with less advanced fibrosis. In these early studies, therapy was stopped after completion of the trial, even for patients who remained HBeAg-positive. Follow-up confirmed that HBV DNA levels rebounded, but rarely did this rebound result in clinically significant flares of hepatitis [17, 18]. In contrast, in those patients with severe fibrosis or cirrhosis at baseline, flares upon treatment withdrawal can result in decompensation [19]. Overall, it appears the risk of an adverse outcome with continuing antiviral therapy during pregnancy is likely very low. However, therapy could be discontinued with close observation of the mother to avoid continued fetal exposure during the first trimester, especially in the patient who does not have advanced fibrosis. Go to:

Rationale for Treatment in the Third Trimester

The majority of perinatal transmission is thought to occur at delivery, because a combination of passive immunization with hepatitis B immunoglobulin (HBIG) given within 12 h of birth and active immunization with three doses of the hepatitis B vaccine in the first 6 months of life resulted in preventing most infections in this setting. Early seminal studies by Beasley et al. [20, 21] showed that HBIG administration could reduce the rate of HBV transmission from more than 90% from HBeAgpositive mothers down to about 26%. When combined with the vaccine, the rates of transmission fell to 3% to 7% [22, 23]. When one looks at the vaccine and HBIG failures, almost all occur in HBeAg-positive women with very high viral loads, generally above 108 copies/mL [24]. A recent report suggested an overall 3% perinatal transmission rate in viremic mothers despite the use of immunoprophylaxis [25]. The rate was as high as 7% in viremic HBeAg-positive mothers and 9% in those mothers who had viral loads greater than 108 copies/mL. This finding raises the question of whether antiviral therapy before delivery would lower the viral load adequately to prevent transmission. Go to:

Evidence for Treatment in the Third Trimester

Should pregnant women who are HBsAg-positive and highly viremic receive antiviral therapy in the third trimester to prevent perinatal transmission? No consensus on this issue has yet been reached [7]. The principal of treatment late in pregnancy to prevent or reduce the rate of perinatal transmission has been established with other viruses. In HIV-infected mothers, the effect of antiretroviral agents (including lamivudine) on the reduction of mother-to-child transmission of HIV was shown to be efficacious [26]. Antivirals have also been advocated late in pregnancy to prevent acquisition of neonatal herpes [27]. In a pilot study, eight women with HBV DNA levels greater than 109 copies/mL were given lamivudine at 34 weeks of gestation. Babies were vaccinated and received HBIG at birth, and only one became infected, compared to 7 of 25 (28%) cases of transmission in a matched historical control population [28]. This finding led to a randomized, double-blind, placebocontrolled trial of lamivudine to prevent transmission in highly viremic HBeAg-positive women [29]. At 1 year of age, 18% of babies of lamivudine-treated mothers were HBsAg-positive compared to 39% in the placebo-treated arm. Both groups received vaccination and HBIG. Based on these results, the authors recommended treatment in the third trimester for women with high viral loads. Unfortunately, because of major problems with loss to follow-up, the data are extremely hard to interpret. At 1 year,

13% of babies in the lamivudine arm and 31% in the placebo arm were lost to follow-up. Evaluating only those with complete data, there was a trend but no significant difference in the rate of HBsAg positivity at 1 year (6% lamivudine vs 12% placebo, P = 0.37). The study was also underpowered (power = 53%), because of slow recruitment. No consequences were reported to mother or baby with lamivudine treatment in the study. More recently, a meta-analysis was reported to evaluate the efficacy of lamivudine in reducing in utero transmission of HBV [30]. A total of 10 randomized controlled trials (RCTs) examining 951 HBV-carrier mothers were included [29, 3139]. The RCTs evaluated included newborns who received immunoprophylaxis at birth and women who were treated with lamivudine from 24 to 32 weeks of gestation, until delivery to 1 month post-delivery. Newborns in the lamivudine group had a 13% to 24% significantly lower incidence of intrauterine exposure, indicated by newborn HBsAg (P = 0.04) and HBV DNA (P < 0.001) positivity. In addition, newborns in the lamivudine treated group had a 1.4% to 2% lower perinatal infection rate at 9 to 12 months, as indicated by HBsAg (P < 0.01) and HBV DNA (P < 0.001) seropositivity. This report was limited by the quality of the studies included (most studies were only rated 3 of 5 on the Jadad scale [40]) and the heterogeneity of the definition used for high viral load that prompted therapy. In a recent study of 31 pregnant women in China, treatment with telbivudine was commenced between 28 and 32 weeks and was continued to 30 days postpartum [41]. Compared with 30 pregnant patients who did not receive therapy and had similar viral loads at baseline and at parturition, the viral loads in the patients treated with telbivudine were reduced significantly, from 7.38 log10 at baseline to 4.08 log10 prior to parturition (P < 0.01). All babies received active and passive immunoprophylaxis. The infection rate was 0% in those treated with telbivudine and 13.3% in the untreated controls. No comparable data exist on efficacy of tenofovir in this area. However, given its potency, tenofovir would be expected to be at least equally as effective as lamivudine in reducing perinatal transmission. This characteristic, together with its high barrier to resistance, makes it an attractive agent to consider in the third trimester. Although treatment in the third trimester would be anticipated to result in a significant lowering of the viral load (which would help prevent perinatal transmission), this result has not been clearly shown and remains controversial. In addition, although a high viral load is clearly important, it is not the only factor predisposing to failure of immunoprophylaxis. This is highlighted by a case in which a child developed chronic HBV infection, despite suppression of HBV DNA to undetectable levels in the mother with lamivudine therapy throughout gestation and appropriate immunoprophylaxis after birth [42]. Rarely, infection may occur in utero, particularly in the setting of threatened preterm labor with very high maternal viral loads [43]. Furthermore, longterm safety data are lacking, and potential risks to the mother include the development of antiviral resistance (relatively unlikely, given the short duration of therapy) and flare of hepatitis after treatment withdrawal. In one study, 42% of those who did not receive antiviral therapy during pregnancy experienced a flare in the postpartum period, compared to 62% among those who had been treated and then discontinued therapy at delivery [44]. Go to:

Algorithm for Management of HBV in the Pregnant Patient

An algorithm for the management and treatment of HBV in pregnancy is proposed in Fig. 1. Routine antepartum care includes testing a woman for the presence or absence of hepatitis B in the first trimester. If she is negative, her child will be vaccinated at birth. The mother does not have to be vaccinated during pregnancy, although it is considered safe and should therefore be administered to those with high-risk behavior for acquisition.

Fig. 1 An algorithm for management of hepatitis B virus (HBV) in the pregnant patient. ALTalanine transaminase; HBcAb hepatitis B core antibody (total); HBeAbhepatitis B e antibody; HBeAghepatitis B e antigen; HBsAbhepatitis ... For those who test positive early in pregnancy, an assessment of the mothers HBV status should occur, including a hepatic panel, HBV serologies, and platelet count. If the patient has very active HBV (significantly elevated ALT with a high viral load), or if cirrhosis is suspected (low platelet count or suggestive imaging), then therapy should be initiated regardless of trimester.

However, if therapy is not warranted (inactive disease with low ALT and low viral load), continued surveillance is suggested because pregnancy can result in a flare of hepatitis B, later in pregnancy and for several months postpartum [16, 44]. Subsequently, it is recommended that all women have their HBV DNA viral load quantified toward the end of the second trimester (at 2628 weeks gestation) so that a final decision regarding therapy can occur shortly thereafter. This assessment will allow enough time in the third trimester to significantly drop the viral load after therapy is initiated to decrease the perinatal transmission rate. Women with high viral loads (>107 copies/mL) should consider initiating therapy early in the third trimester (2830 weeks), after a thorough discussion of the risks and benefits, because data are too limited to mandate therapy. Once started, therapy is continued for the duration of the pregnancy and can be discontinued postpartum if desired. The decision to discontinue therapy is often influenced by the womans desire for subsequent pregnancies. The timing of therapy discontinuation postpartum remains unclear. In published studies, therapy is discontinued anywhere from birth to 1 month after delivery [30]. In practice, therapy is often continued up to 6 months postpartum. Regardless of when therapy is discontinued, a small but real risk of flare exists, and the mother should be monitored closely after withdrawal for at least 6 months. Another factor that may influence the timing of treatment discontinuation postpartum is the mothers desire to breastfeed. Few data are available regarding the safety of breastfeeding while on antiviral therapy; thus, breastfeeding while on treatment for HBV is not recommended [45, 46]. When deciding on therapy in the third trimester, the perinatal transmission outcome of prior pregnancies must be considered. If previous pregnancies did not result in perinatal transmission, then a viral load of greater than 10 7 copies/mL should be used to determine if therapy should be initiated (similar to the woman who has had no previous children). However, if perinatal transmission did occur with a prior pregnancy, then the risk of perinatal transmission in the current pregnancy is likely higher [7]. In such cases, strong consideration for initiating therapy in the third trimester is recommended, regardless of the mothers viral load at the end of the second trimester. Go to:

Transmission of HBV Infection in Breastfed Babies

Although early studies claimed that HBV transmission could occur through breast milk, more recent studies have shown similar rates of acquisition, regardless of whether babies were fed with breast milk or formula. In 1975, before the availability of neonatal immunization, the rates of acquisition of HBV were found to be 53% in breast-fed and 60% in formula-fed babies born to HBsAg-positive mothers [47]. These data are limited because the high vertical transmission rates confounded the true rate of acquisition from breastfeeding. After the introduction of immunoprophylaxis, Hill et al. [48] found a similar rate of infection in breast-fed and formula-fed infants (0% and 3%). Thus, current guidelines state that breastfeeding is not contraindicated in HBV-infected mothers who are not on antiviral therapy whose infants receive immunoprophylaxis [3]. For mothers on antiviral therapy, breastfeeding is not recommended. According to prescribing information, it has not been recommended that women breastfeed their infants while taking lamivudine or tenofovir, to avoid risking postnatal transmission of HIV-1 infection [45, 46]. Although it is known that lamivudine and tenofovir are both excreted into human breast milk, little is known about the extent of exposure of antiviral agents during breastfeeding. Thus, little is known about the overall safety of breastfeeding in this setting. Go to:

Conclusions
Factors to consider when deciding whether HBV therapy is warranted for either the woman of childbearing age or the pregnant woman include extent of existing liver disease, efficacy, and safety of existing FDA-approved antiviral agents. Although none of these agents are approved for use in this setting, data are emerging regarding safety. With increasing data, fewer delays occur in treating pregnant women who have clinically active disease. However, it remains unclear if therapy is beneficial when initiated in the third trimester in highly viremic mothers. Additional studies are needed to address this question.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2945465/

Expert Opin Pharmacother. 2009 Dec;10(17):2801-9. doi: 10.1517/14656560903304071.

Treatment of viral hepatitis in pregnancy.

Fiore S1, Savasi V.
Author information Abstract
Viral hepatitis can be caused by the hepatitis A, B, C, D and E viruses. In the Western world, hepatitis A, B or C do not seem to influence the course of pregnancy, whereas hepatitis E infection, when contracted during the second or third trimester, seems to have a higher risk of developing into a fulminant hepatitis. Mother-to-infant transmission of hepatitis A seems to be very uncommon. The majority of HBsAg-positive and HBeAg-positive mothers can transmit the disease vertically. The timing of transmission is predominantly peripartum, and newborns of HBsAg-positive mothers should receive hepatitis B immunoglobulins within 12 h of birth, with HBV vaccine at birth and 1 and 6 months later. Hepatitis C is more often a chronic disease. Vertical transmission of hepatitis C is considered to be relatively rare but high viraemia or coinfection with HIV can increase this risk. There is currently no treatment to prevent this vertical transmission and pregnancies among HCV-positive mothers should not be discouraged. Infants should be tested for anti-HCV at 1 year and followed for the development of hepatitis. Breast feeding does not seem to play an important role in the transmission of hepatitis B and C.

Eur J Immunol. 2003 Dec;33(12):3342-52.

Breaking tolerance in hepatitis B surface antigen (HBsAg) transgenic mice by vaccination with cross-reactive, natural HBsAg variants.
Schirmbeck R1, Dikopoulos N, Kwissa M, Leithuser F, Lamberth K, Buus S, Melber K, Reimann J.
Author information Abstract
Processing exogenous hepatitis B surface antigen (HBsAg) of the hepatitis B virus (HBV) generates the K(b)-binding S(208-215) epitope 1; processing endogenous HBsAg generates the K(b)-binding S(190-197) epitope 2. Cross-reactive CD8(+) T cell responses were primed to epitope 1 but not epitope 2 when mice were immunized with natural HBsAg(ayw), or HBsAg(adw2) variants differing within both epitopes by one or two residues. Expression of HBsAg(ayw) from a transgene in the liver renders (HBs-tg) mice tolerant to epitope 1 of HBsAg(ayw). CD8(+) T cells specific for epitope 1 could be primed in HBs-tg mice by HBsAg(adw2); these specific CD8(+) T cells cross-reacted with epitope 1 processed from the transgene-encoded HBsAg(ayw). The liver of vaccinated HBsAg(ayw) transgenic mice showed severe histopathology and contained functional (IFNgamma-producing), cross-reactive CD8(+) T cells, and vaccinated HBs-tg mice showed reduced antigenemia. Hence, vaccination with natural HBsAg variants from different HBV sero/genotypes can prime cross-reactive, specific CD8(+) T cell immunity that breaks tolerance to HBsAg.

Case 1: Discussion
Recommendations for HIV Testing in Pregnancy

The Centers for Disease Control and Prevention (CDC), the American Academy of Pediatrics, and the American College of Obstetricians and Gynecologists (ACOG) recommend offering HIV testing to all pregnant women as part of routine antenatal laboratory testing, using an "opt-out" approach, meaning that pregnant women will undergo testing for HIV as part of the routine prenatal laboratory evaluation unless they refuse the test[1,2,3]. The ACOG also recommends offering repeat testing in the third trimester to women from high HIV prevalence areas, those with risk behaviors for acquiring HIV, and those who declined testing earlier in the pregnancy[ 3]. If the pregnant woman refuses HIV testing, the clinician should document this refusal in the medical record. The conventional HIV testing algorithm used for women during pregnancy involves screening with the enzyme-linked immunoassay (ELISA) and confirming any positive test with a Western blot or an immunofluorescence assay (IFA). Because this conventional process of HIV testing can require several days, or even several weeks in some centers, it is not acceptable to use conventional HIV tests for women with undocumented HIV status who present at the time of labor; in this setting, rapid HIV testing is the appropriate testing method.

Impact of Antiretroviral Therapy on HIV Transmission

Antiretroviral therapy and avoidance of breastfeeding are the primary interventions that reduce the risk of mother-to-child HIV transmission. In 1994, results from the Pediatric AIDS Clinical Trials Group (PACTG) 076 trial were published showing a multi-component zidovudine (Retrovir) regimen reduced mother-to-child HIV transmission by nearly 70%[4]. Later that year, the U.S. Public Health Service (USPHS) issued guidelines for the use of zidovudine to reduce perinatal HIV transmission. The PACTG 076 study and the subsequent USPHS recommendations spurred a dramatic decline in the number of perinatal AIDS cases in the late1990's[1]. Clinical trials and observational studies in the United States, as well as clinical trials of shorter course regimens in low resource settings, have demonstrated that a variety of antiretroviral regimens reduce the risk of maternal-child HIV transmission, with the greatest risk reductions seen with longer duration and more complex regimens (Figure 1)[1,4,5,6,7]. With the use of combination antiretroviral therapy during pregnancy and the achievement of very low or undetectable maternal HIV RNA levels (at the time of delivery or near delivery), perinatal transmission of HIV occurs in fewer than 1-2% of women, in contrast with the transmission rate of 20-25% in women who receive no antiretroviral therapy (Figure 2)[1]. The use of antiretroviral therapy may provide significant benefit even if the

pregnant woman does not achieve an undetectable HIV RNA level. Among women with comparable low-level detectable HIV RNA (less than 1,000 copies/ml) at the time of delivery, those who received antiretroviral therapy (during pregnancy, at the time of delivery, or both) had a significantly lower rate of HIV transmission compared with those who received no antiretroviral therapy[8]. Thus, it appears that antiretroviral therapy decreases maternal-child HIV transmission via multiple mechanisms, including those dependent and independent of HIV RNA levels. Taken together, available data clearly show that antiretroviral therapy significantly reduces the risk of maternal to child HIV transmission, and these data justify recommendations to use antiretroviral therapy for all HIV-infected pregnant women during pregnancy.

Guidelines for Use of Antiretroviral Therapy in Pregnancy

The USPHS guidelines discuss four major clinical scenarios in which antiretroviral therapy can be used to reduce maternal to child transmission of HIV: (1) an HIV-infected pregnant woman has not received prior antiretroviral therapy; (2) an HIV-infected woman is receiving antiretroviral therapy that was started before she became pregnant; (3) an HIV-infected woman is in labor and has not received prior antiretroviral therapy; and (4) an infant is born to an HIV-infected woman who has received no antiretroviral therapy during pregnancy or in the intrapartum period. The following discussion will focus on management issues related to the first two scenarios that involve the use of antiretroviral therapy during pregnancy. All HIV-infected pregnant women, regardless of what regimen they receive during pregnancy, should receive intravenous zidovudine during labor, and the newborn should receive zidovudine by oral suspension for the first 6 weeks of life[1].

Approach to Antiretroviral Therapy-Na?ve Pregnant Woman

When an antiretroviral therapy-na?ve HIV-infected woman becomes pregnant or is newly diagnosed with HIV in pregnancy, she should promptly undergo clinical, immunologic, and virologic evaluation. In this scenario, many experts would recommend deferring initiation of antiretroviral therapy until after the first trimester to minimize fetal exposure at the most vulnerable period of development. If, however, the clinical or immunologic condition of the woman indicates the need for more immediate initiation of therapy, effective combination antiretroviral therapy should be started, using agents as recommended in the 2005 US Public Health Service (USPHS) Task Force document (discussed below in Specific Drug Recommendations for Use in Pregnancy)[1]. In addition, some experts would recommend obtaining baseline genotypic resistance testing prior to selecting an antiretroviral regimen. When the pre-antiretroviral therapy HIV RNA level exceeds 1000 copies/ml, combination antiretroviral therapy is recommended, regardless of the patient's CD4 cell count or clinical status. In addition, the pregnant woman should receive combination antiretroviral therapy if she has an indication for antiretroviral therapy based on her immunologic status. Although zidovudine monotherapy with the three-part regimen used in the PACTG 076 study 3 would be considered acceptable in women who have a CD4 count greater than 350 cells/mm and HIV RNA less than 1000 copies/ml, data from PACTG 367 suggest that combination therapy achieves an even lower rate of HIV transmission[9]. In addition, the use of zidovudine monotherapy during pregnancy can result in the development of resistance to zidovudine and can thus negatively affect future antiretroviral therapy options.

Approach to Pregnant Woman Receiving Antiretroviral Therapy

In the second scenario involving an HIV-infected woman who becomes pregnant while taking antiretroviral therapy, most experts would recommend continuing therapy, especially if the woman has already entered the second or third trimester of pregnancy. If, however, the woman is still in the first trimester, the risks and benefits of continuing therapy should be discussed in detail withher[1]. In some instances, antiretroviral therapy may need to be interrupted in the first trimester if the woman has significant nausea and vomiting, a situation that may create problems with adherence and proper absorption. If, for whatever reason, antiretroviral therapy is discontinued during the first trimester, all antiretroviral medications should be stopped to avoid the development of resistance and then restarted at the onset of the second trimester. If the regimen includes efavirenz (Sustiva) or nevirapine (Viramune), most experts would recommend discontinuing these drugs several days prior to other medications in the regimen because of their very long half-life and low genetic barrier to developing resistance[1]; in this situation, the clinician should ideally consult with an expert in antiretroviral therapy. If the decision is made to continue antiretroviral therapy during the first trimester, and the woman's existing regimen contains efavirenz, another effective agent should replace efavirenz, because of the increased risk of neural tube defects associated with first trimester exposure to this drug[10,11]. Some experts would consider the use of efavirenz in the second or third trimester acceptable if no other effective antiretroviral option existed. In addition, if therapy is to be continued, but the existing regimen does not include zidovudine, many experts would recommend substituting zidovudine for one of the nucleoside (or nucleotide) reverse transcriptase inhibitors (if this would be likely to maintain optimal effectiveness) or adding zidovudine to an existing regimen, mainly because of the extensive data with zidovudine in preventing maternal-child HIV transmission.

Specific Drug Recommendations for Use in Pregnancy

Most of the same general principles exist when choosing antiretroviral regimens for use during pregnancy as when choosing regimens for HIV-infected adults and adolescents who are not pregnant. The 2005 USPHS Task Force recommended antiretroviral therapy for HIVinfected pregnant women consists of combination therapy with three or more antiretroviral medications, typically two nucleoside reverse transcriptase inhibitors (NRTIs) plus a protease inhibitor (PI). These guidelines categorize antiretroviral drugs in pregnancy as either recommended, alternative, those for which insufficient data exists, and those not recommended (Figure 3)[1]. These categorizations are based on experience (or lack of experience) and available data with these medications related to safety and effectiveness in reducing perinatal HIV transmission. Any decision regarding regimen selection should also include consideration of effectiveness for maternal treatment. The preferred dual NRTI backbone consists of zidovudine combined with lamivudine ( Epivir), most often given as the fixeddrug preparation Combivir. The preferred PIs include either nelfinavir (Viracept) or saquinavir SGC (Fortovase) boosted with ritonavir (Norvir). As noted above, the use of efavirenz should be avoided during pregnancy. Although the use of single or dual NRTIs alone is not recommended for treatment of HIV infection, zidovudine monotherapy is considered acceptable for prophylaxis of perinatal transmission in pregnant women who have a baseline HIV RNA less than 1,000 copies/mL and who do not meet CD4 criteria for initiating antiretroviral treatment. The clinician should also be aware of several special considerations when using antiretroviral agents in pregnancy: (1) pharmacokinetics may be altered during pregnancy; (2) antiretroviral therapy toxicity and side effects may be altered in pregnancy, or may be more easily overlooked; and (3) potential fetal and newborn toxicity, such as birth defects, carcinogenicity, anemia, and mitochondrial toxicity, must be considered, since these could potentially occur with babies exposed to these drugs in utero, irrespective of their HIV status.

Special Risk with Antiretroviral Therapy During Pregnancy

Women initiating nevirapine with a CD4 greater than 250 cells/mm have a 10-fold increased risk of developing symptomatic, often rash-associated hepatotoxicity and hepatic failure, usually within the first 18 weeks after starting nevirapine[1,12,13,14]. These adverse reactions to nevirapine have included several deaths among pregnant patients. Although women who enter pregnancy on a welltolerated nevirapine-containing regimen may continue on this regimen, initiating nevirapine-containing combination therapy in women 3 with a CD4 count greater than 250 cells/mm should be avoided. Although it is recommended that whenever possible antenatal antiretroviral therapy should include zidovudine as part of the regimen, zidovudine is associated with bone marrow suppression and pregnant women are more likely to be anemic. Accordingly, severe anemia constitutes a relative contraindication for using zidovudine, unless a transfusion is given. Stavudine (Zerit) is considered an alternative NRTI in pregnancy and can substitute for zidovudine, as in the patient in this case. The combination of stavudine and didanosine ( Videx EC) has been associated with several cases of lactic acidosis, some fatal, in pregnancy and should not be used unless no other options areavailable[15,16]. Sparse data exist regarding the use of tenofovir DF (Viread), abacavir (Ziagen), or emtricitabine (Emtriva) during pregnancy. Tenofovir DF has become a very commonly
3

used agent for non-pregnant HIV-infected persons, but its use in pregnancy remains limited because of concern regarding potential fetal bone effects. Among the protease inhibitors, there are some concerns with indinavir ( Crixivan) and atazanavir (Reyataz) use late in pregnancy, mainly because these drugs can increase indirect bilirubin levels and thus theoretically exacerbate physiologic hyperbilirubinemia in the neonate. Although there are concerns with maternal toxicity resulting from antiretroviral therapy, the benefits of therapy in preventing perinatal transmission and improving maternal health when maternal treatment is indicated far outweigh the risks. [Back to Case 1 Question | See Case 1 References]

https://depts.washington.edu/hivaids/perinatal/case1/discussion.html