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The pharmacokinetics, safety and efficacy of tenofovirand emtricitabine in HIV-1-infected pregnant women

Angela P.H. Colbersa, David A. Hawkinsb, Andrea Gingelmaierc,

Kabamba Kabeyad, Jurgen K. Rockstrohe, Christopher Wyenf,

Katharina Weizsackerg, S. Tariq Sadiqh, Jelena Ivanovici,

Carlo Giaquintoj, Graham P. Taylork, Jose Moltol,

David M. Burgera, on behalf of the PANNA network

Objectivtrimeste

Methodanalogu300 mg;were incthe thirCollectiPharmacStatistica

Results:third trimTDF are0.90) foFTC Cmathan 200weeks. Areported

Concluspregnanin this s

Keywo

aRadboucKlinikumBelgiumBerlin, GRome, jUGerman

CorrespoGrootep

Tel: +31Received

DOI:10.d University Nijmegen Medical Centre, Nijmegen, The Netherlands, bChelsea & Westminster Hospital, London, UK,der Universitat Munchen, Frauenklinik Innenstadt, Munich, Germany, dSaint-Pierre University Hospital, Brussels,

, eUniversity of Bonn, Bonn, fUniversity of Cologne, Cologne, gKlinik fur Geburtsmedizin, Charite Universitatsmedizin,ermany, hSt. Georges, University of London, London, UK, iNational Institute for Infectious Diseases L. Spallanzani,niversity of Padua, Padova, Italy, kImperial College Healthcare NHS Trust, London, UK, and lHospital Universitari

s Trias I Pujol, Badalona, Spain.

ndence to Angela Colbers, MSc, Department of Pharmacy, Radboud University Nijmegen Medical Centre, Geertlein Zuid 10, 6525 GA Nijmegen, The Netherlands.

24 3616405; fax: +31 24 3668755; e-mail: a.colbers@akf.umcn.nl: 18 September 2012; revised: 22 October 2012; accepted: 31 October 2012.

1097/QAD.0b013e32835c208b

ISSN 0269-9370 Q 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins 739child transmission, pharmacokineticight Lippincs: HIV-infected pregnant women treated with the nucleotide/nucleosidee reverse transcriptase inhibitors (NRTIs) tenofovir disoproxil fumarate (TDFequivalent to 245 mg tenofovir disoproxil) and/or emtricitabine (FTC 200 mg)luded in the study. Twenty-four-hour pharmacokinetic curves were recorded ind trimester (preferably week 33) and postpartum (preferably week 46).on of a cord blood sample and maternal sample at delivery was optional.okinetic parameters were calculated using WinNonlin software version 5.3.l analysis was conducted using SPSS version 16.0.

Thirty-four women were included in the analysis. Geometric mean ratios ofester vs. postpartum [90% confidence interval (CI)] were 0.77 (0.710.83) for

a under the curve (AUC024 h); 0.81 (0.680.96) for TDF Cmax and 0.79 (0.70r TDF C24 h and 0.75 (0.680.82) for FTC AUC024 h; and 0.87 (0.770.99) for

x and 0.77 (0.521.12) for FTC C24 h. The viral load close to delivery was lesscopies/ml in all but one patient, the average gestational age at delivery was 38ll children were tested HIV-negative and no congenital abnormalities were

.

ion: Although pharmacokinetic exposure of the NRTIs TDF and FTC duringcy is approximately 25% lower, this was not associated with virological failuretudy and did not result in mother-to-child transmission.

2013 Wolters Kluwer Health | Lippincott Williams & Wilkins

AIDS 2013, 27:739748

rds: combination antiretroviral therapy, emtricitabine, HIV, mother-to-s, pregnancy, tenofovirpregnant women recruited from HIV treatment c

Design: A nonrandomized, open-label, multicentre phase IV study in HIV-infected

entres in Europe.e: To describe the pharmacokinetics of tenofovir and emtricitabine in the thirdr of pregnant HIV-infected women and at postpartum.ott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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Introduction

In 2010, approximately 17.5 million women wereinfectedage [1].infectedfuture, w[2]. ThiHIV in

Combinshownmother-the riskDepartmrecommanalogugood trafeasiblezidovudof thecompouantiretro1995 andisoprox30%, wapproximmendaticombinacross theproductbe consion theexposurand terabased) dwith angestationAmerica

The antto 31 Jathe riskdefects owith 2.Europeaof pyeleTDF-codescribevery higoffsprin[23,24],with FTanomalido not

Humanaffecting

mostly resulting in lower exposure of medicationduring pregnancy.

rmafovractsosurcurpregtudiet ofer

e becentnic

lts [1pregen

plinFV

rmae benitu

[26]. When 400 mg is administered at labouriation, the plasma concentrations appear higher thanr chronic administration of 200 mg FTC in non-nan

infonannannannan

tho

s wastud

HorkEur

inetinanlved

ecteary

stuciplsentringicallvedyber

740 AIDS 2013, Vol 27 No 5t Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.with HIV, most of who were of child-bearingIt is estimated that 39% of the European womenwith HIV have a desire for childbearing in thehich is comparable to HIV-uninfected women

s has also been reported for women infected withthe USA [3] and South Africa [4].

ation antiretroviral therapy (cART) has beento be a highly effective strategy for preventingto-child transmission (PMTCT) of HIV, reducing

from 1540 to less than 2% [5]. The USent of Health and Human Services guidelinesend the inclusion of one or more nucleosidee reverse transcriptase inhibitors (NRTIs) withnsplacental passage in the cART regimen, when[6]. The most commonly used NRTIs are

ine (ZDV) and lamivudine (3TC), mainly becausevastly greater clinical experience with thesends during pregnancy. However, an overview ofviral drugs prescribed during pregnancy betweend 2009 showed an increase in the use of tenofoviril (TDF)/emtricitabine (FTC) to approximatelyhereas the use of ZDV/3TC decreased fromately 90 to 70% [7]. This reflects the recom-

ons for first-line NRTI backbone (TDF/FTCtion) in nonpregnant adults [8]. All four NRTIsplacenta well [914]. The current summary of

characteristics of Truvada [15] states that its usemaydered during pregnancy, if necessary. Safety issuesuse of antiretrovirals during pregnancy concerne of the mother, influence on pregnancy durationtogenicity. cARTuse (especially protease inhibitoruring pregnancy has been reported to be associatedincreased rate of preterm delivery (

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Patient eligibility included being HIV infected, pregnant,at least 18 years of age at screening and treated with acARTregimen containing TDF and/or FTC for at least 2weeks bevaluatiwere exconditiodistribufailure oanaemiaat screen

SafetyInclusioexaminaqualitaticount. Alocal labwere fursamplinPatientsDAIDSreportedwas coll

PharmaA 24-h2 weekstrimestepostpartdeliverysampleTFVandof the PMedical

A standto (obsemillilitre(predosemedicatstudy dalower ufor anal

AnalytiConcenby use ochromat

SampleextractioShield Rflow ratusinglemission(LOQ)plasma w

Sample preparation for FTC consisted of a solid-phaseextraction. One hundred and ninety microlitres of thesolution was injected onto an Atlantis CP18 column

m,ml/mctor

Q wma wdated

rmacomarsiga un, thplepleinat

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tistients for whom a curve was taken during pregnancye included in demographic, safety analyses andriptive statistics of the pharmacokinetic parameters.metentstpartrted

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Tenofovir and emtricitabine in pregnancy Colbers et al. 741efore the day of first pharmacokinetic curveon (in the third trimester of pregnancy). Patientscluded if they had a past medical history or currentn that might interfere with drug absorption,

tion, metabolism or excretion (such as renalr hepatic failure) or presented with grade III/IV(i.e. haemoglobin

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A totaltrimestepostparttotal of 224 postpwith TDdeterminot havwithdra

742 AIDS 2013, Vol 27 No 5

Table 1. Patient characteristics.

Age at delivery [years, median (range)] 32 (1944)Race/ethnicity [n (%)]

White 16 (47)Black 17 (50)Other 1 (3)

Smoking [n (%)] 7 (21)Alcohol use [n (%)] 4 (12)

Truvada use [n (%)] 31 (91)Treatment naive at start of pregnancy [n (%)] 11 (32)ARV treatment duration before pregnancy [months, median (range)] 50 (2135)Concomitant ARVs [n (%)]

Protease inhibitors 24 (71) (11 atazanavir/r, 10 darunavir/r, 2 lopinavir/r,2 saquinavir/r, 1 fosamprenavir/r)

NNRTI 6 (18) (4 nevirapine, 2 efavirenz)Raltegravir 2 (6)RategravirPI 1 (3)MaravirocPI 1 (3)

Third trimester (N34)Gestational age [weeks, median (range)] 33 (2838)WeightHIV-RNCD4 ceCreatinCreatin

PostpartuTime aWeightHIV-RNCD4 ceCreatinCreatin

PregnancGestatiCaesareBirth wInfant V

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)

Fig. 1. M[kg, median (range)]A undetectable

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19 and 21% lower during pregnancy compared withpostpartum (intrasubject comparison). For FTC, theAUC024 h, Cmax, C24 h were 25, 13 and 23% lower,respectivduring prespectivsamplesFTC AUbetween

In Fig.during tsubdivisNNRTNo diffeobserve

Sixteen umbilical cord blood samples were collected withmatching maternal blood samples. In one cord bloodsample (and the matching maternal sample), FTC/TFV

centeen

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10)

cacvi

ation272very

Tenofovir and emtricitabine in pregnancy Colbers et al. 743

Table 2. Pharmacokinetic parameters.

Third trimestera Postpartuma GM ratio (90% CI) of thirdtrimester : postpartum

Pb

Tenofovir n34 n27 n27AUC024 h (mg h/l) 2.46 (2.232.66) 3.17 (2.863.52) 0.77 (0.710.83)

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tested HIV-negative and no congenital abnormalitieswere reported. Four of the infants (12%) were bornbetween 36 and 37 weeks gestational age. Three babieshad a low birth weight (50 copies/ml) foratients around delivery. Five out of the sevenwith a detectable viral load were on cART beforecy (one on NNRTI-based cART and four oninhibitor-based cART) and two started treat-

ring pregnancy (protease inhibitor-based cART);tment duration was 24 and 28 weeks at deliverye latter two patients. Adherence was checked bywhether the patients had been taking theirion according to prescription for the last 2 weeks

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ts with and without detectable viral load aroundetectable viral load.sion

tudy, we evaluated the pharmacokinetics of TFV, in the majority of cases combined in Truvada,

pregnant HIV-infected patients, at the thirdr of pregnancy and after delivery. In the thirdr of pregnancy, a decrease in TFV AUC024 h,d C24 h (23, 19 and 21%, respectively) was

d as well as a decrease in FTC AUC024 h, Cmaxh (25, 13 and 23%, respectively). The clearance) was markedly increased during pregnancy formpounds (TFV 30% and FTC 34%).

d FTC are mainly excreted unchanged in urine,g that renal clearance is the major route ofion. It is known that renal clearance is increasedpregnancy [36], in line with our findings thatd creatinine clearance increased during preg-y around 40%. Although possibly influencing thed exposure during pregnancy found in this study,not translated into shorter half-life of TFV andeproduction of this article is prohibited.

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interval, which is possibly not a correct estimate, becausethe last sample was taken 24 h after dosing, this means thatthe entire elimination phase was not covered.

Otherreducedplasma vproteindecreaseimplyinpossiblythe absoand afte

Proteasetrationspatientsproteasefindingpregnaninhibitonumberin this sdetect a

There ipreviouAUC0nant coFTC ofnormalshowedmeet thonly 4%the patiein the tOne ofthresholcomparthresholAUC0controlsmothermission

The ref3.324 m0.064 memtricit1.86 mgThe tenkineticreferenccharacteparametas referethe pregpresent

The decreased FTC AUC and C24 h observed in this studyis in line with the decrease reported by Stek et al. [26].However, we also observed a decrease in FTC Cmax,

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Tenofovir and emtricitabine in pregnancy Colbers et al. 745physiological changes during pregnancy areintestinal motility, increased gastric pH, a largerolume, increased hepatic blood flow, decreased

binding and induced hepatic enzymes. The Cmaxd by 19% for TFV and 13% for FTC, potentiallyg the influence of larger plasma volume anddecreased gastrointestinal absorption. However,rption was not delayed, as Tmax was similar duringr pregnancy for both compounds.

inhibitors are known to increase TFV concen-[37]. In this study, the TFV AUC024 h foron an NNRTI regimen are similar to these on ainhibitor regimen. Possible explanations for thiscould be a decrease in boosting effect duringcy because of the lower exposure to proteasers during pregnancy [9,38,39]; furthermore, theof patients using a nonprotease inhibitor regimentudy was low (only 18%), reducing the power todifference.

s no efficacy threshold level for TFV or FTC. Ins studies with TDF, a threshold of 2 mg h/l for24 h [6] (being the 10th percentile of nonpreg-ntrols) was used and an AUC024 h threshold for

at least 7 mg h/l (30% reduction from thecontrols) [26]. Using these thresholds, the studythat 26% of the patients receiving TDF did note threshold in the third trimester compared with

of the patients in the postpartum period. Fornts on FTC, only 4% did not meet the thresholdhird trimester compared with 0% postpartum.nine of patients with TFV AUC024 h below thed had a detectable viral load around delivery,ed with six of 25 with AUC024 h above thed. This finding indicates that in this study, TFV

24 h below the 10th percentile of nonpregnantwas not associated with virological failure of theand did not result in mother-to-child trans-(MTCT).

erence tenofovir AUC in nonpregnant adults isg h/l with a Cmax of 0.326 mg/l, a Cmin ofg/l and a Thalf of 1218 h [4042]. The referenceabine AUC is 10.0 mg h/l with a Cmax of/l, a Cmin of 0.09 mg/l and a Thalf of 10 h [28].ofovir and emtricitabine postpartum pharmaco-parameters found in this study are in line withe values reported in the summary productristics. This implies that pharmacokineticers recorded 5 weeks after delivery can be usednce values for the nonpregnant situation, that isnancy induced physiological changes were notanymore.

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er NRTIs (zidovudine, lamivudine, didanosineavir), pharmacokinetic studies during pregnancyrted decreased exposure, without a need for dose

n [4346].

h compounds, placenta passage is good, concen-in the cord blood are somewhat lower for TFVroximately similar to the concentrations of thefor FTC. This is in line with the findings of other[47]. In this review, cord blood : maternal ratioscompounds ranged from 0.60 to 1.6 (with anf 6.0 for tenofovir).

al load was undetectable (

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variation in European and non-European ethnicitiesavailable for investigation: approximately 50% whiteEuropean and 50% black patients were included.

A limitawas collthird trthoughtthe promore, isuppressimportaconcenteffect oassessingof pregn

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UNAmed20125 JFiorRepEuroFinocchario-Kessler S, Sweat MD, Dariotis JK, Trent ME,Kerrigan DL, Keller JM, et al. Understanding high fertilitydesires and intentions among a sample of urban womenlivin14:1

4. SchwHightiencanAIDHarenhlancimm199DHHPregandtheaidsSeptGrinet alHIVAIDDHHInfeaidsmenMiroals107

746 AIDS 2013, Vol 27 No 5he staff from the centres participating in thenetwork (not mentioned in the authors list):

MC Rotterdam, The Netherlands: Dr M.E. vane.

l Virgen de las Nieves, Granada, Spain:lgo.

isericordiae University Hospital Dublin, Ireland:mbert.

d University Nijmegen Medical Centre, Nijme-e Netherlands: Dr A.J.A.M. van der Ven and Dris.

isch Medisch Centrum, Amsterdam, The Neth-Dr J. Nellen.

5.

6.

7.

8.

9.tion of the study is that no pharmacokinetic curveected in the second trimester. We focused on theimester as drug disposition of antiretrovirals isto be most affected during this period, because of

minent physiological changes present. Further-n the phase close to delivery, maximum viralion and antiretroviral effectiveness is considerednt in order to minimize MTCT. Subtherapeuticrations in late pregnancy may have a negativen antiviral efficacy. This is also a reason for

drug exposure during the third trimesterancy.

usion, although pharmacokinetic exposure of theTDF and FTC during pregnancy is approximatelyer, this was not associated with virological failuretudy and did not result in MTCT.

wledgements

.G. and D.B. are the primary authors whoed and designed the study. D.H., A.G., K.K., J.R.,.W., S.T.S,. J.I., G.T. and J.M. were directlyin the design and conduct of the PANNA study

luded patients on TDF and/or FTC. A.C. wasy responsible for conducting analyses of the datawriting of the manuscript. All authors collectivelyted to interpreting results and drafting and

of the paper.

k the patients for participating in this study and

Ma

CoSounetwTreDGCT-

C.WIngMyJanshonAbbhonBoePfiz

A.CJ.H

Re

1.

2.

3.t Lippincott Williams & Wilkins. Unauthorized rg with HIV in the United States. AIDS Behav 2010;1061114.artz SR, Mehta SH, Taha TE, Rees HV, Venter F, Black V.pregnancy intentions and missed opportunities for pa-

tprovider communication about fertility in a South Afri-cohort of HIV-positive women on antiretroviral therapy.S Behav 2012; 16:6978.ris NS, Fowler MG, Sansom SL, Ruffo N, Lampe MA. Use ofanced perinatal human immunodeficiency virus surveil-e methods to assess antiretroviral use and perinatal humanunodeficiency virus transmission in the United States,92001. Am J Obstet Gynecol 2007; 197:S33S41.

S. Recommendations for Use of Antiretroviral Drugs innant HIV-1-Infected Women for Maternal HealthInterventions to Reduce Perinatal HIV Transmission inUnited States; 14 September 2011; pp 1207. http://info.nih.gov/contentfiles/PerinatalGL.pdf. [Accessed 1ember 2012]er R, Williams PL, Read JS, Seage GR, Crain M, Yogev R,. In utero and postnatal exposure to antiretrovirals among-exposed but uninfected children in the United States.S Patient Care STDS 2011; 25:385394.

S. Guidelines for the Use of Antiretroviral Agents in HIV-1-cted Adults and Adolescents, version 27 March 2012. http://info.nih.gov/guidelines/html/1/adult-and-adolescent-treat-t-guidelines/0/2012. [Accessed 30 May 2012]chnick M, Capparelli E. Pharmacokinetics of antiretrovir-in pregnant women. Clin Pharmacokinet 2004; 43:

11087.ermany: A. Haberl.

ts of interestsupport that requires acknowledgement: The PANNAis financially supported by the European AIDS

nt Network (NEAT), European Commission,earch, 6th Framework program, contract LSHP-6-037570, BMS and MSD.

as received consulting fees from Boehringerm, fees for speaking engagements from Bristol-quibb, Gilead Sciences, ViiV Healthcare, MSD,Cilag, Essex, Pfizer and Abbott. D.B. has receivedia and/or study grants from Tibotec, Merck,BMS, Roche, Gilead and GSK. J.R. has receivedia for consulting or speaking fees from Abbott,ger, BMS, Bionor, Gilead, GSK, Janssen, Merck,ibotec and ViiV.

.H., A.G., K.K., K.W., S.T.S., J.I., C.G., G.T. ande no conflicts of interest to declare.

nces

IDS. AIDS epidemic update. http://www.unaids.org/en/ia/unaids/contentassets/documents/unaidspublication/1/JC2216_WorldAIDSday_report_2011_en.pdf. [Accesseduly 2012]e S, Heard I, Thorne C, Savasi V, Coll O, Malyuta R, et al.roductive experience of HIV-infected women living inpe. Hum Reprod 2008; 23:21402144.eproduction of this article is prohibited.

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10. Burchett S, Best B, Mirochnick M, Hu C, Capparelli E, FletcherC, et al. Tenofovir pharmacokinetics during pregnancy, atdelivery and post partum. In: Proceedings of the 14th Confer-ence on Retroviruses and Opportunistic Infections; 2528 Feb-ruar

11. MiroNierateandRetrMon

12. Rodet arateProcportabst

13. FlynFiscandandof tInfe939

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15. EMAww_Pro201

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19. APRterimwwSep

20. EURwwbles

21. SabConnofocase

22. TaraFetato gDefi

23. NurAdvwom158

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25. VanAbeto rpregviro52:3

26. StekEffeMed

27. Flynn PM, Mirochnick M, Shapiro DE, Bardeguez A, Rodman J,Robbins B, et al. Pharmacokinetics and safety of single-dosetenofovir disoproxil fumarate and emtricitabine in HIV-1-in-fected pregnant women and their infants. Antimicrob AgentsCheEMAww_Pro[AccAndneti200Dawneti15:8AbdSoltwithparamodBenPregpopmotBestdoseneti15th36HirtPopmunthei106Holassuals:colother367MayNepKiseTM,anc200RoukinepregvanHIV200EMAww_Pro[AccBlummacratevoluRamneticoarateSynMooLeeuof lain hwomBestHolcokWanGanandnanstud

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w.apregistry.com/forms/interim_report.pdf. [Accessed 1tember 2012]OCAT. EUROCAT prevalence data tables. http://

w.eurocat-network.eu/accessprevalencedata/prevalenceta-. [Accessed 7 September 2012]batini F, Prati F, Borghi V, Bedini A, Esposito R, Mussini C.genital pyelectasis in children born from mothers on te-vir containing therapy during pregnancy: report of twos. Infection 2007; 35:474476.ntal AF, Castillo A, Ekert JE, Bischofberger N, Martin RB.l and maternal outcome after administration of tenofovirravid rhesus monkeys (Macaca mulatta). J Acquir Immunec Syndr 2002; 29:207220.utdinova D, Onen NF, Hayes E, Mondy K, Overton ET.erse effects of tenofovir use in HIV-infected pregnanten and their infants. Ann Pharmacother 2008; 42:

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748 AIDS 2013, Vol 27 No 5t Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

The pharmacokinetics, safety and efficacy of tenofovir and emtricitabine in HIV-1-infected pregnantwomenIntroductionMethodsSafety assessments and viral loadPharmacokinetic blood samplingAnalytical and pharmacokinetic methodsStatistical analysis data handling

ResultsPharmacokineticsEfficacy and safetyPharmacokinetics-efficacy relationship

DiscussionAcknowledgementsConflicts of interest