Safety of Tenofovir During Pregnancy for the Mother and Fetus: A Systematic Review

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1 REVIEWARTICLE HIV/AIDS Safety of Tenofovir During Pregnancy for the Mother and Fetus: A Systematic Review Liming Wang, 1 Athena P. Kourtis, 2 Sascha Ellington, 2 Jennifer Legardy-Williams, 2 and Marc Bulterys 1,3 1 Global AIDS Program, Centers for Disease Control and Prevention, Beijing, China; and 2 Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, and 3 Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia Tenofovir disoproxil fumarate (TDF) safety during pregnancy has important public health implications. This review summarizes TDF safety during pregnancy, focusing on pregnancy outcomes, congenital anomaly risk, and other potential toxicities on neonates. Although information is limited, TDF appears to be safe during pregnancy. In 6 studies of human immunodeficiency virus type 1 (and/or hepatitis B virus) infected women receiving TDF during pregnancy, adverse events were mild to moderate; none were considered to be TDF-related. Five studies that followed in utero TDF-exposed infants showed no increased risk of growth or bone abnormalities. One showed slightly lower infant height at age 1 year, but the significance is unclear. The Antiretroviral Pregnancy Registry database, with 1800 pregnancies exposed to TDF in the first trimester, does not indicate increased congenital anomaly risk with TDF. More evidence collected prospectively, ideally with bone density measurements and randomized trial design, will be optimal to determine the effects of antenatal TDF on children s health. Keywords. HIV; PMTCT; TDF; pregnancy; safety. Mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) can be substantially reduced by using antiretroviral therapy during pregnancy, labor and delivery, and breastfeeding [1 4]. Highly effective antiretroviral therapy (HAART) during pregnancy can reduce the HIV-1 MTCT rate to as low as 1% 2%, even in developing countries [2 4], and is now recommended for prevention of MTCT (PMTCT) by the World Health Organization [5]. Tenofovir disoproxil fumarate (TDF) is a potent nucleotide analogue reverse transcriptase inhibitor (NRTI) that has become a first-line backbone agent in HAART regimens due to its once-daily dosing and excellent efficacy and tolerability profiles [6 8]. More recently, TDF Received 25 June 2013; accepted 31 August 2013; electronically published 17 September Correspondence: Athena P. Kourtis, MD, PhD, MPH, Women s Health and Fertility Branch, Division of Reproductive Health, Centers for Disease Control and Prevention, 4770 Buford Hwy NE, MS-K34, Atlanta, GA (apk3@cdc.gov). Clinical Infectious Diseases 2013;57(12): Published by Oxford University Press on behalf of the Infectious Diseases Society of America This work is written by (a) Government employee(s) and is in the public domain in the. DOI: /cid/cit601 has been shown to be efficacious in preventing sexual transmission of HIV-1 in uninfected adults ( pre prophylaxis) [9 12]. In addition, TDF has also potent activity against hepatitis B virus (HBV) infection and is approved for its treatment [13 15]. Given the increasing use of TDF in treating HIV-1 (and/or HBV) and in pre prophylaxis, the chance of being exposed to TDF at the time of conception or during pregnancy is increasing substantially [16]. The Food and Drug Administration has classified TDF as a Pregnancy Category B drug, meaning there is no adequate evidence of risk in humans. Due to the limited safety information of TDF during pregnancy, the present Perinatal Guidelines recommend TDF to be the first-line agent to treat HIV- 1/HBV-coinfected [17]. For HIV- 1 infected, HBV-uninfected, antiretroviral-naive pregnant women, TDF is only recommended as an alternative NRTI [17]. Therefore, obtaining safety information on TDF during pregnancy has important public health implications. The aim of this review is to provide a systematic summary from the literature on TDF use in pregnancy, with a focus on the safety profile of prenatal use of HIV/AIDS CID 2013:57 (15 December) 1773

2 TDF for the mothers and infants, including the adverse events and outcomes, risk of congenital anomalies for infants exposed in utero, and other potentially toxic effects in the neonates (growth, bone, or other abnormalities). METHODS We searched PubMed on 6 August 2013 and reviewed all English-language literature published up until that time using the search terms of pregnancy, gestation, antenatal, prenatal, fetal, fetus, neonate, infant, intrauterine, and tenofovir or tenofovir disoproxil fumarate. We examined the abstracts of all identified articles; if no abstract was available, the full article was examined. When the abstract included clinical information for on any form of TDF for any length of time, and when it contained original information (not a review), we considered the article relevant. We only looked at articles in peer-reviewed journals (including articles published online ahead of print) and did not attempt to identify unpublished articles such as abstracts at conferences. In addition, we also reviewed the most recent interim report of the Antiretroviral Pregnancy Registry (APR) [18]. APR is the largest safety database for antiretroviral drugs in pregnancy. It is a prospective, voluntary registration system collecting information from health providers aiming at detecting any major teratogenic or other toxic effect of antiretroviral drugs. RESULTS We identified 130 nonduplicate journal articles, and 111 were excluded due to lack of relevance. Among the remaining 19 articles, 3 pertained to TDF in rhesus macaques [19 21] and 16 pertained to humans [18, 22 36]. These included case reports, case series, retrospective or prospective observational studies, and clinical trials. Prenatal and Postpartum TDF Exposure in Animal Studies Three articles were found in the literature reporting on the safety of prenatal and postnatal TDF use among rhesus macaques [19 21]. Maternal administration of a high dose of TDF (30 mg/kg/day) did not impair fetal growth in utero. Sonographic assessments showed normal growth patterns in fetuses regardless of whether maternal treatment was initiated during the first [19] or the second trimester [20]. However, if the same dose of TDF was given to infant rhesus macaques postnatally, one-quarter of experimental infants developed severe growth restriction and reduction of bone porosity [20]. Further studies showed that these toxicities tended to occur at high-dose and long-term s rather than short-term high-dose or prolonged low-dose s [21]. For infants with maternal to similar doses of TDF starting from the first trimester, birth crown rump length and birth weight were either below or at the lower range of normal compared with age-matched controls [19]. There were also significantly lower serum insulin-like growth factor 1 (IGF-1) concentrations in fetuses, which could explain the observed low growth at delivery [19]. Prenatal TDF Use in Humans Safety Profile of TDF for Pregnant Women Because patients exposed to single-dose nevirapine frequently develop nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) resistance [37], several studies attempted to evaluate a short course of TDF/emtricitabine (FTC) at labor and delivery and the early postpartum period for PMTCT and prevention of antiretroviral drug resistance development. In the trial in Zambia, women were randomized at labor to either the local standard-of-care regimen (short-course zidovudine and singledose nevirapine) or single-dose TDF/FTC plus the local standard of care. The results showed that NNRTI resistance development was significantly decreased in the TDF/FTC arm at both 2 and 6 weeks postpartum [22]. Mothers and infants had a similar proportion of serious adverse event (SAEs) occurrence in both groups: mothers, 4% in the TDF/FTC arm and 5% in the control arm; infants, 10% in the TDF/FTC arm and 12% in the control arm [22]. ne of the SAEs were judged to be attributable to TDF use [22]. In the Tenofovir Emtricitabine in Africa and Asia (TEmAA) trial, TDF/FTC (600 mg/400 mg), given to the mothers starting from the onset of labor until 7 days postpartum, was well tolerated and resulted in no peripartum HIV-1 transmissions [23]. maternal drug resistance to NNRTIs or NRTIs was observed [23]. In the second phase of the same trial, single-dose TDF/FTC (TDF 13 mg/kg and FTC 2 mg/kg) was provided to neonates within 12 hours of life. The results also showed no peripartum HIV-1 transmissions [24]. The observed SAEs (eg, grade 3 anemia, gastroenteritis, respiratory symptoms) were not thought to be TDF-related [24]. A pharmacokinetic of 28 HIV-1 infected women in the United States who received single-dose TDF (either 600 mg or 900 mg) at labor found that both mothers and infants tolerated TDF well without TDF-associated SAEs reported [25]. In addition to the above studies, there are other studies where TDF was used for longer periods of time. In an evaluation of 127 HIV-1 infected women receiving HAART during pregnancy, 15 women received a TDF-based regimen with a median in utero TDF of 127 days [26]. TDF was generally well tolerated in this. Although 73% (11/15) of the women on TDF experienced laboratory abnormalities, none were attributable to TDF [26]. In a European, 34 HIV- 1 infected receiving TDF and/or FTC before 1774 CID 2013:57 (15 December) HIV/AIDS

3 and during pregnancy were evaluated; the median antiretroviral treatment duration before delivery was 50 months, and no TDF-related SAEs were reported [27]. In the Development of AntiRetroviral Therapy in Africa (DART) Trial conducted in Uganda and Zambia, no significant difference was found in the distribution of miscarriages/terminations, stillbirths, and live births between on TDF (111 patients) vs those not on TDF (62 patients) [28]. In an Italian of trends of antiretroviral use during pregnancy and pregnancy outcomes in , a significant increase in the use of TDF/FTC was found from almost none in 2005 to >10% in [29]. During the same period, a similar increasing trend was observed in the United States [30]. This increased use of TDF/FTC was not accompanied by changes in preterm delivery, Apgar scores of newborn infants, birth weight, or congenital anomalies at the population level [29]. Because no information was provided at the individual level in these 2 articles, they were not further included in this review. We identified only 1 where TDF was used in HBVmonoinfected mothers. Eleven mothers with high HBV viremia received daily oral TDF 300 mg during the third trimester [31]. In addition to HBV vaccine and hepatitis B immune globulin administered to the exposed newborn babies, TDF appeared to be effective in preventing HBV transmission to the infant with no adverse pregnancy outcomes and/or congenital anomalies [31]. Use of TDF 1% vaginal gel precoitally was demonstrated to lower the risk of HIV-1 acquisition sexually by 39% in 1 in South Africa [12].Women may become pregnant while on TDF gel for preventing HIV-1 infection; a investigating the pharmacokinetics and placental transfer of TDF vaginal gel showed that single-dose 1% TDF vaginal gel in term pregnancy resulted in very low TDF concentrations in maternal serum and did not result in any safety issues [32]. Table 1 lists all studies that reported on TDF safety during pregnancy or in the perinatal period. Teratogenicity APR was the main source of data on teratogenic effects related to antiretroviral drugs [18]. Each year, there are approximately 1300 enrolled, representing 15% 20% of HIV-1 infected women who give birth to live infants annually in the United States. The most recent APR interim report was issued in June A total of pregnancies and outcomes after to antiretroviral drugs at any time during pregnancy from 1 January 1989 through 31 January 2013 were reported [18]. The overall congenital anomaly rate with to any antiretroviral agent at any time during pregnancy was 2.9 per 100 live births (95% confidence interval [CI], 2.6% 3.2%) [18], which was not significantly different from the prevalence of congenital anomalies of 2.7% reported by the Centers for Disease Control and Prevention congenital anomalies surveillance system [18]. For TDF in particular, the prevalence of congenital anomalies reported was 2.3% (42/1800; 95% CI, 1.7% 3.1%) with during the first trimester, and 2.4% (20/894; 95% CI, 1.4% 3.4%) with during the second/third trimester. There were sufficient numbers of first-trimester s to TDF to detect at least a 1.5-fold increase in risk of overall congenital anomalies and a 2-fold increase in risk of congenital anomalies in the more common classes, such as cardiovascular and genitourinary system defects. such increases have been detected to date, nor was any specific pattern of major congenital anomalies observed. However, we should note that the registry might not always provide sufficient information about the specific nature of congenital anomalies. Although 2 cases of pyelectasis, a dilation of the renal pelvis, were reported in children exposed to maternal TDF during pregnancy [33], this may not be considered a congenital anomaly as it usually resolves spontaneously. Furthermore, there are no studies in the literature so far showing an association of TDF use during pregnancy with increased risk of teratogenicity. In the DART trial, congenital anomalies were reported in 3% of TDF-exposed and 4% of non-tdf-exposed live births [28]. In the European mentioned earlier, there were no congenital anomalies reported among any of the infants born to 31 TDF/FTC-treated HIV-1 infected mothers [27]. Fetal Growth and Bone Health Decreases in bone mineral density have been observed with use of TDF in macaques (intravenously) [19, 20] and humans (orally) [7, 38, 39]. In light of this concern, studies to explore fetal/infant bone and growth outcomes after TDF during pregnancy are needed. Currently, the information is very limited. In the case series mentioned previously by Nurutdinova et al [26], growth was assessed by measuring birth weight and reviewing growth charts during follow-up visits. The results showed that the majority of infants (14/15) with in utero TDF had normal growth development both at birth and at 12 months of age. One infant failed to thrive due to parental neglect. In the DART trial, no significant evidence of lower birth weight or other growth parameters up to age 4 years and no fractures during follow-up were reported among 120 children who were exposed to TDF prenatally [28]. A multicenter observational, which included 68 infants exposed to HAART in utero, indicated that in utero to TDF did not impair growth and bone health in HIV-1 uninfected infants [34]. Similar distribution of low weight and length measurements were found between groups with or without in utero to TDF both at birth and at a median age of 23 months [34]. Bone mineral status was measured by quantitative ultrasound; axially transmitted tibial speed of HIV/AIDS CID 2013:57 (15 December) 1775

4 1776 CID 2013:57 (15 December) HIV/AIDS Table 1. Studies That Reported on Safety of Tenofovir Use in Pregnant Women and Their Infants, Reference Study Type Country Study Population Chi et al 2007 [22] Arrive et al 2009 [23] Arrive et al 2010 [24] Flynn et al 2011 [25] Kinai et al 2012 [36] Pan et al 2012 [31] RCT Zambia 397-HIV infected and their 397 infants Multicenter openlabel phase 1/2 trial (step 1) Multicenter openlabel phase 2/3 Trial (step 2) Pharmacokinetic Cote d Ivoire, Cambodia, and South Africa Cote d Ivoire, Cambodia, and South Africa, Puerto Rico 38 women infected with HIV-1 or HIV-2 and their 39 infants 36 women infected with HIV-1 and their 36 infants 28 HIV-infected mothers and their 26 infants Case report Japan One HIV-infected woman Retrospective case series 11 HBVmonoinfected Intervention Serious Adverse Events SAE Is Related to Mothers Infants Mothers Infants TDF 198 of 397 women received peripartum sd of TDF/ FTC + intrapartum sd NVP + short course of ZDV from 32 wk gestation 38 women received twicedaily ZDV from 28 wk gestation + sd NVP + 2 tablets of TDF/FTC at delivery, and once-daily TDF/FTC for 7 d postpartum Twice-daily ZDV from 28 wk gestation + sd NVP + 2 tablets of TDF/FTC at delivery, and once-daily TDF/FTC for 7 d postpartum 13 women received sd of 600 mg TDF at labor + standard ZDV prophylaxis intravenously and 15 women received sd of 900 mg TDF (8 with FTC and 7 without FTC) at labor Abacavir + LPV/ r + raltegravir in the first 33 wk of pregnancy with change to abacavir + LPV/ r + TDF at 35 wk gestation (3 wk prior to delivery) TDF 300 mg daily during the third trimester sd NVP within 72 h of birth and ZDV for 7 d sd NVP on the first day of life and twice-daily ZDV for 7 d sd NVP on the first day of life + twicedaily ZDV for 7 d + single dose of TDF/FTC within 12 h of life 10 infants were exposed to TDF prenatally; 7 infants received 4 mg/kg of TDF only after birth and 9 infants received 4 mg/kg of TDF plus 3 mg/kg of FTC after birth NA Hepatitis B immune globulin at birth; HBV vaccine at birth, 1 mo and 6 mo postpartum 4% (7/198) had SAEs The most common SAE was postpartum anemia 23.7% (9/38) had SAEs postpartum Anemia (3) Neutropenia (5) Liver enzyme elevation 5.6% (2/36) had SAEs postpartum Grade 3 leukopenia Grade 4 neutropenia 10.8% (20/198) in the TDF-exposed group had SAEs; Most common causes of morbidity were septicemia (22) and pneumonia (8) 28.2% (11/39) had SAEs Deaths (3) Anemia (3) Viral bronchopneumonia Streptococcus pneumonia, meningitis Ophthalmia neonatorum (2) Neonatal sepsis and urinary tract infection 13.9% (5/36) had SAEs Death due to infection Acute brain injury at birth Grade 3 neutropenia Grade 3/4 hyperbilirubinemia (2) ne Grade 3 anemia Modest proximal tubular dysfunction Decreased fetal growth, biparietal diameters, and femur length ne ne NA Unknown

5 Table 1 continued. HIV/AIDS CID 2013:57 (15 December) 1777 Reference Study Type Country Study Population Beigi et al 2011 [32] Sabbatini et al 2007 [33] Nurutdinova et al 2008 [26] Vigano et al 2011 [34] Colbers et al 2013 [27] Gibb et al 2012 [28] Pharmacokinetic Retrospective case series Retrospective case series Multicenter observational nrandomized open-label multicenter phase 4 RCT Italy Italy Europe Uganda Zimbabwe 16 HIV-uninfected women 33 HIV-infected mothers and their 33 infants 127 pregnancies in HIV-infected women 68 mothers taking HAART during pregnancy 34 HIV-infected and their 34 infants 382 pregnancies in 302 HIV-infected and their 226 live infants Intervention Serious Adverse Events SAE Is Related to Mothers Infants Mothers Infants TDF 1% TDF vaginal gel single use in term pregnancy 7 of 33 women received TDF as their regimens were continued during pregnancy 15 women (16 pregnancies) received TDF either as part of treatment or for prevention of mother-tochild transmission of HIV HAART that included TDF was initiated from second or third trimester with a median duration of of 25 wk 34 women received TDF and/or FTC as part of HAART during pregnancy for at least 2 wk 120 of 182 pregnancies included in the analysis received a TDF-containing regimen NA ne NA NA 7 infants with 15 infants had 33 of 68 infants had 34 infants had 120 infants included in the analysis had ne 73% (11/15) experienced laboratory abnormalities One case with SAE (grade 3 hyperbilirubinemia) 2 of 7 patients with in utero TDF reported congenital pyelectasis One fetal death due to maternal chorioamnionitis One failed to thrive due to parental neglect Unknown ne ne NA 5.9% (2/34) developed SAEs Postpartum anemia due to blood loss during delivery Postnatal uterine atony ne NA 3% (7/226) had congenital abnormalities (no difference in TDF exposed and nonexposed infants, P =.69) 10% (22/225) were premature (no difference in TDF exposed and nonexposed infants, P =.67) 16% (34/209) had low birth weight (no difference in TDF exposed and nonexposed infants, P =.44) 10% (6/62) with no in utero TDF and 6% (7/111) with in utero TDF died (P =.42)

6 Table 1 continued. Intervention Serious Adverse Events SAE Is Related to Mothers Infants Mothers Infants TDF Reference Study Type Country Study Population NA 19.5% with TDF and 19.1% without TDF had low birth weight (OR = 0.87, P =.40) 8.3% with TDF and 8.6% without TDF were small for gestational age (OR = 1.04, P =.88) 426 infants had 449 mothers received TDF during pregnancy including 263 who used TDF during first trimester 2029 HIV-exposed uninfected children whose mothers received antiretrovirals with or without TDF Prospective cohort Siberry et al 2012 [35] Abbreviations: FTC, emtricitabine; HAART, highly effective antiretroviral therapy; HBV, hepatitis B virus; HIV, human immunodeficiency virus; LPV/r, lopinavir/ritonavir; NA, not applicable; NVP, nevirapine; OR, odds ratio; RCT, randomized controlled trial; SAE, severe adverse event; sd, single dose; TDF, tenofovir; ZDV, zidovudine. sound was similar in the 2 groups [34]. In addition, unlike the finding in the macaque [19], infants exposed to TDF had IGF-1 serum concentration comparable to those of unexposed infants [34]. Lower serum concentrations of parathyroid hormone and higher urinary calcium excretion were detected in the exposed group, but all values were within the reference range for age [34]. However, this had a relatively small sample size (33 infants in the TDF-exposed group and 35 infants in the nonexposed group), and the subjects age when enrolled and evaluated was months. This could lead to selection bias and does not allow for evaluation of differences at birth that may change over time. Data analysis of a large cohort of 2029 children (426 of whom had antenatal to TDF) in the Pediatric HIV/AIDS Cohort Study (PHACS) showed that maternal TDF use during pregnancy did not impair fetal growth at birth but may have had a delayed effect on infant growth 1 year later [35]. The mechanisms and significance of this finding are not yet fully understood [16, 35]. In addition, a case report from Japan noted blunted fetal biparietal diameter and femur length after the mother started TDF at 35 weeks of gestation until delivery at 38 weeks [36]. Despite lower weight and height at birth and throughout the first 3 months of life, there was no sign of osteomalacia or rickets detected later on [36]. The causal link is unclear given late and short to TDF. Currently, no published has evaluated bone density measurements to assess bone development in TDF-exposed infants. Table 2 lists a summary of studies reporting effects of TDF use during pregnancy on infant growth and bone health. Other Toxicities Postmarketing surveillance has reported nephrotoxicity in patients receiving TDF, but the majority of these patients were adults and had preexisting risk factors for renal insufficiency [38, 40]. Therefore, TDF dosage modification is required for patients whose creatinine clearance (CrCl) is <50 ml/min [41]. rmally, CrCl may increase by as much as 50% in pregnancy because of increased glomerular filtration rate and renal plasma flow [42]. Data from a pooled analysis of 5 clinical trials in Malawi found that only 0.4% of HIV-1 infected had a baseline CrCl <50 ml/min, suggesting that assessment of baseline CrCl may not be necessary before TDF initiation in pregnancy in resource-limited settings [43]. Mitochondrial toxicity, presenting with a variety of clinical symptoms such as lactic acidosis, liver steatosis, pancreatitis, lipodystrophy, or myopathy, is a potential adverse effect of NRTI use [44, 45] due to possible inhibition of DNA polymerase-γ [46, 47]. There are no human data linking TDF use in pregnancy with emergence of mitochondrial toxicity. An in vitro showed that TDF is a weaker inhibitor of DNA 1778 CID 2013:57 (15 December) HIV/AIDS

7 polymerase-γ than most of the other NRTIs, and it was not concentration dependent; therefore, TDF is less likely to cause mitochondrial toxicities [48]. Toxicities of TDF in Pregnant Women Infected With HBV The use of antiviral approaches during pregnancy has been suggested as a complementary means of minimizing MTCT of HBV, particularly among women with high HBV DNA loads and e antigen (HBeAg) expression, in whom rates of breakthrough HBV transmission to the infant despite immunization can be high [49, 50]. Lamivudine and telbivudine have been evaluated in late pregnancy among HBV-infected women to prevent vertical transmission in a few studies [50 54], but TDF has not yet been evaluated. As mentioned before, a small cohort of 11 Asian HBV-monoinfected, HBeAg-positive pregnant women were treated with TDF in the third trimester [31]. After a median duration of 10 weeks, a significant reduction in serum HBV DNA was achieved at delivery. HBV MTCT occurred, and no obstetric complications or congenital anomalies were observed. In HIV-1/HBV-coinfected individuals, elevation in liver enzymes can occur after initiation of antiretroviral drugs, particularly in those with low CD4 + T-cell counts and advanced immunosuppression, as a result of immune reconstitution [55]. Such immune-mediated flares can also occur postpartum in HBV-monoinfected women, even in the absence of therapy [56, 57]. Pregnant women who are started on TDF-based regimens should be counseled about signs and symptoms of liver toxicity, and liver enzymes should be assessed regularly after antiretroviral drug initiation. Differentiation between HBV disease flare or drug toxicity can be difficult and requires expert consultation for further management. Five ongoing clinical trials (NCT , NCT , NCT , NCT , NCT ) in women monoinfected with HBV or coinfected with HIV-1 and HBV will hopefully shed more light on the safety of TDF use during pregnancy. Table 2. Summary of Studies Reporting Potential Effects of Tenofovir Used in Pregnancy on Infant Growth and Bone Health, Reference Study Country Study Population. of Infants Exposed to TDF Infant Growth and Bone Health Nurutdinova et al 2008 [26] Vigano et al 2011 [34] Siberry et al 2012 [35] Gibb et al 2012 [28] Kinai et al 2012 [36] Retrospective case series Multicenter observational Prospective cohort Randomized controlled trial Italy Uganda, Zimbabwe 127 pregnancies in HIV-infected women who received HAART with or without TDF 68 HIV-exposed uninfected infants born to mothers who received HAART with or without TDF 2029 HIV-exposed uninfected children whose mothers received maternal ARV with or without TDF 382 pregnancies in 302 HIVinfected who took HAART with or without TDF during pregnancy Case report Japan One case with in utero TDF between 35 and 38 wk of gestation 14 live infants with antenatal TDF 33 exposed to maternal TDF 426 with maternal TDF use 120 with in utero TDF One rmal growth and development at birth and during 12-month follow-up One failed to thrive due to parental neglect difference in incidence of LBW and length in TDF-exposed and unexposed groups difference in small for gestational age, LBW, birth length for age, or birth head circumference for age z scores with TDF Slightly decreased infant length at 1 y of age among those with in utero TDF (mean z scores of length-forage at 1 year of age: 0.17 vs 0.03, P =.04) z scores for weight, mid-upper arm circumference, and head circumference for age were not different in children with or without in utero TDF at birth or during follow-up Height-for-age z scores were similar in TDF-exposed and nonexposed groups during 2 y follow-up bone fractures reported during 2 y of follow-up Lower weight and height at birth and throughout the first 3 mo of life sign of osteomalacia or rickets detected by hand radiography at 1 and 3 mo of age Abbreviations: ARV, antiretroviral; HAART, highly effective antiretroviral therapy; HIV, human immunodeficiency virus; LBW, low birth weight; TDF, tenofovir. HIV/AIDS CID 2013:57 (15 December) 1779

8 CONCLIONS Our systematic review indicates that TDF appears to be generally safe for HIV-1 (and/or HBV) infected. The available safety data of TDF in pregnancy are generally reassuring for pregnancy outcomes and for lack of congenital or other severe anomalies in exposed infants. The evidence on the effects of TDF on bone health and growth of infants is limited but also generally reassuring, in contrast to data from animal studies, where extremely high doses and prolonged use might have led to the adverse outcomes observed. However, the PHACS suggested slightly lower mean length and head circumference at 1 year of age among infants exposed to maternal TDF in utero [35], and a case of blunted fetal growth in an infant exposed to TDF for a brief period of time during late gestation was reported from Japan [36]. Therefore, more research on the safety of TDF in pregnancy is needed. Prospectively collected data, randomized designs, and maternal/infant bone density measurements would be particularly useful. Research on the long-term effects of antenatal TDF on child health will also be necessary. Given the anticipated increase in TDF use among and the rapidly changing antiretroviral drug use guidance, the need for and importance of such studies are urgent and compelling. tes Acknowledgments. The authors thank Jessica Chung, MPH, and Chin- Yih Ou, PhD, for help with the electronic search and editorial assistance. Author contributions. L. W. and A. P. K. did the electronic search and identified eligible studies. L. W. wrote the first draft. All authors contributed to subsequent drafts. All authors read and approved the final draft of the manuscript. Disclaimer. The opinions expressed in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention. Potential conflicts of interest. All authors: reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Read JS. Prevention of mother-to-child transmission of HIV: antiretroviral strategies. Clin Perinatol 2010; 37: Thomas TK, Masaba R, Borkowf CB, et al. Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding the Kisumu Breastfeeding Study, Kenya: a clinical trial. PLoS Med 2011; 8:e Palombi L, Marazzi MC, Voetberg A, Magid NA. Treatment acceleration program and the experience of the DREAM program in prevention of mother-to-child transmission of HIV. AIDS 2007; 21(suppl 4): S Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to reduce HIV-1 transmission. N Engl J Med 2010; 362: World Health Organization. Programmatic update: Use of antiretroviral drugs for treating and preventing HIV infection in infants executive summary. Geneva, Switzerland: WHO, Available at: eng.pdf. Accessed 6 August Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA 2004; 292: Cassetti I, Madruga JV, Suleiman JM, et al. The safety and efficacy of tenofovir DF in combination with lamivudine and efavirenz through 6 years in antiretroviral-naive HIV-1-infected patients. HIV Clin Trials 2007; 8: Nelson MR, Katlama C, Montaner JS, et al. The safety of tenofovir disoproxil fumarate for the treatment of HIV infection in adults: the first 4 years. AIDS 2007; 21: Van Damme L, Corneli A, Ahmed K, et al. Pre prophylaxis for HIV infection among African women. N Engl J Med 2012; 367: Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral pre prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367: Abdool Karim Q, Abdool Karim SS, Frohlich JA, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329: Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med 2008; 359: Liaw YF, Sheen IS, Lee CM, et al. Tenofovir disoproxil fumarate (TDF), emtricitabine/tdf, and entecavir in patients with decompensated chronic hepatitis B liver disease. Hepatology 2011; 53: Murray KF, Szenborn L, Wysocki J, et al. Randomized, placebocontrolled trial of tenofovir disoproxil fumarate in adolescents with chronic hepatitis B. Hepatology 2012; 56: Kuhn L, Bulterys M. Does maternal use of tenofovir during pregnancy affect growth of HIV-exposed uninfected infants? AIDS 2012; 26: Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations 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 Available at: Accessed 6 August Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 January Wilmington, NC: Registry Coordinating Center, Available at: Accessed 6 August 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: 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: 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: Chi BH, Sinkala M, Mbewe F, et al. Single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: an open-label randomised trial. Lancet 2007; 370: Arrive E, Chaix ML, Nerrienet E, et al. Tolerance and viral resistance after single-dose nevirapine with tenofovir and emtricitabine to prevent vertical transmission of HIV-1. AIDS 2009; 23: CID 2013:57 (15 December) HIV/AIDS

9 24. Arrive E, Chaix ML, Nerrienet E, et al. Maternal and neonatal tenofovir and emtricitabine to prevent vertical transmission of HIV-1: tolerance and resistance. AIDS 2010; 24: Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected and their infants. Antimicrob Agents Chemother 2011; 55: Nurutdinova D, Onen NF, Hayes E, Mondy K, Overton ET. Adverse effects of tenofovir use in HIV-infected and their infants. Ann Pharmacother 2008; 42: Colbers A, Hawkins D, Gingelmaier A, et al. The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1 infected. AIDS 2013; 27: 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:e Baroncelli S, Tamburrini E, Ravizza M, et al. Antiretroviral treatment in pregnancy: a six-year perspective on recent trends in prescription patterns, viral load suppression, and pregnancy outcomes. AIDS Patient Care STDS 2009; 23: Griner R, Williams PL, Read JS, et al. In utero and postnatal to antiretrovirals among HIV-exposed but uninfected children in the United States. AIDS Patient Care STDS 2011; 25: Pan CQ, Mi LJ, Bunchorntavakul C, et al. Tenofovir disoproxil fumarate for prevention of vertical transmission of hepatitis B virus infection by highly viremic : a case series. Dig Dis Sci 2012; 57: Beigi R, guchi L, Parsons T, et al. Pharmacokinetics and placental transfer of single-dose tenofovir 1% vaginal gel in term pregnancy. J Infect Dis 2011; 204: Sabbatini F, Prati F, Borghi V, et al. Congenital pyelectasis in children born from mothers on tenofovir containing therapy during pregnancy: report of two cases. Infection 2007; 35: Vigano A, Mora S, Giacomet V, et al. In utero to tenofovir disoproxil fumarate does not impair growth and bone health in HIVuninfected children born to HIV-infected mothers. Antivir Ther 2011; 16: Siberry GK, Williams PL, Mendez H, et al. Safety of tenofovir use during pregnancy: early growth outcomes in HIV-exposed uninfected infants. AIDS 2012; 26: Kinai E, Hosokawa S, Gomibuchi H, et al. Blunted fetal growth by tenofovir in late pregnancy. AIDS 2012; 26: Arrive E, Newell ML, Ekouevi DK, et al. Prevalence of resistance to nevirapine in mothers and children after single-dose to prevent vertical transmission of HIV-1: a meta-analysis. Int J Epidemiol 2007; 36: Lyseng-Williamson KA, Reynolds NA, Plosker GL. Tenofovir disoproxil fumarate: a review of its use in the management of HIV infection. Drugs 2005;65: Grigsby IF, Pham L, Mansky LM, et al. Tenofovir-associated bone density loss. Ther Clin Risk Manag 2010; 6: Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med 2006; 354: World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Geneva, Switzerland: WHO, Available at: /85321/1/ _eng.pdf. Accessed 6 August Sims EA, Krantz KE. Serial studies of renal function during pregnancy and the puerperium in normal women. J Clin Invest 1958; 37: Johnson DC, Chasela C, Maliwichi M, et al. Tenofovir use and renal insufficiency among pregnant and general adult population of HIVinfected, ART-naive individuals in Lilongwe, Malawi. PLoS One 2012; 7:e Brinkman K, ter Hofstede HJ, Burger DM, et al. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. AIDS 1998; 12: Moyle G. Clinical manifestations and management of antiretroviral nucleoside analog-related mitochondrial toxicity. Clin Ther 2000; 22: Kakuda TN. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Clin Ther 2000; 22: Lewis W, Dalakas MC. Mitochondrial toxicity of antiviral drugs. Nat Med 1995; 1: Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 2002; 46: Kourtis AP, Bulterys M, Hu DJ, Jamieson DJ. HIV-HBV coinfection a global challenge. N Engl J Med 2012; 366: Dusheiko G. Interruption of mother-to-infant transmission of hepatitis B: time to include selective antiviral prophylaxis? Lancet 2012; 379: Han L, Zhang HW, Xie JX, et al. A meta-analysis of lamivudine for interruption of mother-to-child transmission of hepatitis B virus. World J Gastroenterol 2011; 17: Deng M, Zhou X, Gao S, et al. The effects of telbivudine in late pregnancy to prevent intrauterine transmission of the hepatitis B virus: a systematic review and meta-analysis. Virol J 2012; 9: Xu WM, Cui YT, Wang L, et al. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled. J Viral Hepat 2009; 16: van Zonneveld M, van Nunen AB, Niesters HG, et al. Lamivudine treatment during pregnancy to prevent perinatal transmission of hepatitis B virus infection. J Viral Hepat 2003; 10: Dusheiko G. Candidates for therapy: HBV. J Hepatol 2006; 44(suppl 1): S Jonas MM. Hepatitis B and pregnancy: an underestimated issue. Liver Int 2009; 29(suppl 1): ter Borg MJ, Leemans WF, de Man RA, et al. Exacerbation of chronic hepatitis B infection after delivery. J Viral Hepat 2008; 15: HIV/AIDS CID 2013:57 (15 December) 1781