Tenofovir disoproxil fumarate in pregnancy and ... - Wiley Online Library

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DOI: 10.1111/j.1468-1293.2009.00709.x HIV Medicine (2009), 10, 397–406

2009 British HIV Association

REVIEWS IN ANTIRETROVIRAL RESEARCH

Tenofovir disoproxil fumarate in pregnancy and prevention of mother-to-child transmission of HIV-1: is it time to move on from zidovudine? C Foster,1 H Lyall,1 B Olmscheid,2 G Pearce,3 S Zhang2 and DM Gibb4 1 Imperial College Healthcare NHS Trust, St Mary’s Campus, London, UK, 2Gilead Sciences Inc., Foster City, CA, USA, 3 Gilead Sciences Europe Ltd., Uxbridge, Middlesex, UK and 4Medical Research Council, London, UK Objectives

Zidovudine (ZDV) has been the cornerstone of antiretroviral (ARV) therapy for pregnant women infected with HIV-1 in the prevention of mother-to-child transmission (MTCT) and remains the only licensed ARV for use in pregnancy. We explored the current and future roles of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT of HIV-1. Methods

We reviewed the published literature by conducting database searches of in vitro, animal and clinical studies, reported in journals and at conferences, using the search terms Tenofovir/gs4331/viread, pregnant/pregnancy, lactate, lactation, natal, reproduce/reproduction, placenta/placental, malformation, and teratogenicity/teratogenic. Results

In a macaque model, perinatal exposure to very high dose tenofovir resulted in bone toxicity in some offspring. However, perinatal use of TDF, both single dose and as part of highly active antiretroviral therapy in women, has been well tolerated in the short term by mothers and their infants. Further, the addition of single-dose TDF to single-dose nevirapine (SD-NVP) during delivery following maternal ZDV use during pregnancy significantly reduces the frequency of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance. Conclusions

The addition of TDF to SD-NVP reduces NNRTI resistance. The role of TDF in this setting and during pregnancy for reducing rates of MTCT requires investigation. While short-term toxicity data are encouraging, long-term follow-up of exposed mothers and infants is required. Keywords: mother-to-child transmission, nevirapine resistance, tenofovir DF, toxicity Accepted 6 February 2009

toxicity [1,2]. Peripartum use of single-dose nevirapine (SD-NVP), the only ARV available for most pregnant women living with HIV-1 world-wide, while effective in reducing MTCT, is associated frequently with the development of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations in both mothers and their infants [3–6]. The widespread use of HAART in resourcerich settings has led to significant reductions in MTCT, with the effects of in utero ART exposure in HIV-uninfected children receiving increasing attention and study [7–10]. With these issues in mind, we explore the current and future roles of tenofovir disoproxil fumarate (TDF) in the prevention of MTCT of HIV-1, reviewing currently available data from in vitro, animal and clinical studies.

Introduction For over a decade, zidovudine (ZDV) has been the cornerstone of antiretroviral therapy (ART) for the prevention of mother-to-child transmission (MTCT) of HIV-1 and, remarkably, it remains the only licensed antiretroviral (ARV) for use during pregnancy. Recent guidelines for treatment-naı¨ve HIV-1-infected nonpregnant adults have seen a shift away from ZDV-based highly active antiretroviral therapy (HAART) because of concerns over Correspondence: Dr C Foster, The Family Clinic, Imperial College NHS Trust, St Mary’s Campus, London W2 1NY, UK. Tel: 1 44 207 886 6096; fax: 1 44 207 886 2341; e-mail: [email protected]/ [email protected]

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398 C Foster et al.

Background During the last 10 years, the risk of MTCT of HIV-1 has fallen from approximately 20% to o1% for women living in well-resourced settings [10–13]. Women aware of their HIV status in early pregnancy can access preventative interventions including the tailored use of ART for mothers and infants, prelabour Caesarean section (PLCS) and infant formula feeding [3,7,11,12]. The beneficial role of ART in the prevention of MTCT was first demonstrated in 1994 in the seminal AIDS Clinical Trials Group 076, which demonstrated a 67% reduction in MTCT with ZDV monotherapy compared with placebo in a nonbreast-feeding population [14]. Despite many developments in HIV treatment over the last 14 years, ZDV remains the only ARV licensed for use in pregnancy [1,15]. While ZDV is a Food and Drug Administration (FDA) Pregnancy Category C drug, many other ARVs, including TDF, have been assigned to the lower risk Pregnancy Category B [4]. Efavirenz (EFV) is currently the only ARV assigned an FDA Category D status [4]. The potential benefit of ARVs other than ZDV in prevention of MTCT was first demonstrated for nevirapine (NVP) in the HIVNET 012 trial, which demonstrated a 47% reduction in MTCT compared with perinatal ZDV use [5]. However, the discovery of high rates of NNRTI HIV-1 resistance mutations in mothers and infected infants following treatment with SD-NVP has precluded its use in regions with access to HAART [6]. In well-resourced settings, significant reductions in MTCT have been seen since the widespread introduction of HAART, with much of the evidence coming from cohort studies [7]. Increasing numbers of women on HAART are choosing to conceive and the vast majority of their infants will be uninfected. Consequently, infants are exposed to an ever-increasing array of ARV drugs in utero, during delivery and for the first 4–6 weeks of life. Minimizing ARV-associated toxicities in these infants has become a priority. Eighty-five per cent of the 2 million pregnant women infected with HIV-1 live in sub-Saharan Africa, where only a minority (37% in 2007) have access to interventions to reduce MTCT [16]. Simple, safe, effective and affordable regimens are urgently required. Despite concerns over NNRTI resistance, SD-NVP continues to play an important role in the prevention of MTCT and strategies aimed at improving upon this intervention have been evaluated [17, 18]. Data from a recent meta-analysis (see Table 1) demonstrate a significant reduction in the development of maternal and infant NNRTI resistance seen with the addition of other ARVs to SD-NVP [6]. The addition of maternal ZDV and lamivudine (3TC) orally to SD-NVP reduces the risk of maternal and infant

NNRTI resistance, although the optimal duration of ZDV/3TC is uncertain [17]. Recommendations based upon these data have been included in the World Health Organization (WHO) Guidelines [19]. More recently, the addition of a single dose of TDF and emtricitabine (FTC) to SD-NVP and short-course ZDV has been shown also to reduce NNRTI resistance [18]. The investigators concluded that SD-TDF/FTC should be considered as an adjuvant to intrapartum NVP [18]. The use of TDF/FTC in this role is discussed below.

Guidelines for the treatment of HIV in pregnant women and for prevention of MTCT Before reviewing data that may guide future treatment recommendations, it is instructive to review current pregnancy guidelines which, not surprisingly, differ between the resource-limited and resource-rich settings. Significant differences also exist among guidelines from the United Kingdom, Europe and the United States [2–4]. The 2008 British HIV Association (BHIVA) Guidelines include ZDV monotherapy with PLCS as a valid option for women with viral loads o10 000 HIV-1 RNA copies/mL and CD4 cell counts 4250 cells/mL [3]. In contrast, the US Public Health Service Task Force (updated 8 July 2008) favours combination antepartum ARV regimens, stating that the use of ZDV monotherapy is controversial, although may be considered for women with HIV-1 plasma viral loads of o1000 copies/mL [4]. For women commencing HAART or short-term triple antiretroviral therapy during pregnancy, the US, BHIVA and European AIDS Clinical Society (EACS) guidelines (updated June 2008) all recommend that ZDV should be included in the regimen where possible [2–4]. Because of the lack of data on the use of TDF in pregnancy and concerns over possible bone toxicity, US guidelines recommend that TDF-based HAART should be used only after careful consideration of alternatives [4]. The EACS guidelines recommend that TDF should not be initiated in pregnancy, although it may be continued if started prior to pregnancy [2]. Toxicity data on the use of ARVs in pregnancy are presented with particular attention to TDF.

Outcomes in ARV-exposed uninfected infants While the benefits of ARVs in preventing MTCT are enormous, areas of concern include possible associations of HAART with premature delivery, risk of congenital abnormalities, association of nucleoside reverse transcriptase inhibitors (NRTIs) with neonatal mitochondrial toxicity, and the theoretical risk of long-term carcinogenicity following in utero exposure to ARVs [20–22].

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2009 British HIV Association HIV Medicine (2009) 10, 397–406

Tenofovir DF in pregnancy and PMTCT of HIV-1 399

Table 1 Prevalence of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations

Maternal

Infant

Arrive et al. (2007) meta-analysis [6]

McIntyre et al. (2005) [17]

Chi et al. (2007) [18]

SD-NVP other antepartum ARVs (10 study arms)

SD-NVP plus additional postpartum ARVs (3 study arms)

SD-NVP

SD-NVP 1 ZDV 1 3TC 4 days

SD-NVP 1 ZDV 1 3TC 7 days

SD-NVP

35.7% (95% CI 23.0– 50.6)

4.5% (95% CI 2.1–9.4)

57%

13%

9%

25%

SD-NVP only (7 study arms)

SD-NVP plus other ARVs (8 study arms)

52.6% (95% CI 37.7– 67.0)

16.5% (95% CI 8.9–28.3)

78%

13%

0%

SD-NVP 1 SD-TDF/FTC 12%, Relative Risk 0.47 (95% CI 0.29–0.76)

ARV, antiretroviral; CI, confidence interval; SD-NVP, single-dose nevirapine; SD-TDF/FTC, single-dose tenofovir disoproxil fumarate/emtricitabine; 3TC, lamivudine; ZDV, zidovudine.

Adverse outcomes, such as preterm delivery (PTD), stillbirth and low birth weight, have been reported in several studies, with indications that these may occur at greater frequency in women on HAART compared with those on mono or dual therapy. The European Collaborative study found combination therapy, but not ZDV monotherapy, to be associated with an increased risk of PTD compared with no treatment [protease inhibitor (PI)-based HAART: odds ratio (OR) 2.6; 95% confidence interval (CI) 1.43–4.75; non-PI-based HAART: OR 1.82; 95% CI 1.13–2.92], an association also reported in a single-centre US study [20, 23]. However, increased rates of PTD with HAART compared with monotherapy were not found in the US-based Women and Infants Transmission Study (WITS) study, although overall rates of prematurity were high at 17% compared with an expected population rate of 6–8% [24]. Cohort data from the United Kingdom and Ireland showed increased rates of PTD with HAART (14% vs. 10% for combined mono/dual therapy) but not specifically PIbased HAART, and a possible association of HAART with low birth weight and stillbirth (adjusted OR 2.27; 95% CI 0.96–5.41; P 5 0.06) compared with mono/dual therapy [21]. A single United Kingdom centre reported an increased rate of PTD associated with initiation of HAART during pregnancy, compared with mono/no ART (OR 5.03; 95% CI 1.4–17.8; P 5 0.01), suggesting that early immune reconstitution may play a role in PTD [25]. The potential for teratogenicity following ARV exposure in pregnancy is of concern as increasing numbers of infants are exposed to ARVs throughout pregnancy, especially during organogenesis in the first trimester. Increasing numbers of new ARV drugs, in both existing and new classes, are prescribed during pregnancy to avoid toxicities of more established drugs, and to fully suppress viraemia in women with resistance mutations.

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The Antiretroviral Pregnancy Register (APR) An important source of data regarding the teratogenicity of ARV drugs is the Antiretroviral Pregnancy Registry (APR) (www.apregistry.com), an international registry established in 1989 to detect major teratogenic effects of ARVs. Registration is prospective, voluntary and confidential through the health care provider, who is encouraged to enrol patients early in pregnancy to maximize the validity of the data, although the APR Advisory Committee does emphasize the limitations of registries based upon voluntary reporting. Reassuringly, the APR has found no overall increase in congenital anomalies. Of 9948 live births prior to 31 July 2008, with exposure at any time during pregnancy, 272 birth defects have been identified, a prevalence of 2.7 per 100 live births (95% CI 2.4–3.1), comparable to the Centers for Disease Control and Prevention surveillance prevalence of birth defects of 2.72 per 100 live births (95% CI 2.68–2.76) [26]. Of the 4329 live births following first trimester ARV exposure, 126 defects were reported (prevalence 2.9 per 100 live births; 95% CI 2.4–3.5). This was comparable to rates reported with initial ARV exposure during the second and/or third trimester (prevalence 2.6 per 100 live births; 95% CI 2.2–3.0; prevalence ratio 1.13; 95% CI 0.89–1.43) [26].

Individual drugs in the APR Regarding the effects of individual ARVs, the APR states: In analyzing individual drugs with sufficient data to warrant a separate analysis, no increases in risk have been detected with the exception of didanosine (ddI) during previous years. No pattern of birth defects has been detected with ddI, and no new reports of defects

400 C Foster et al.

with ddI exposure have been received in recent reporting periods [26]. For abacavir, atazanavir, EFV, emtricitabine, indinavir, lopinavir, nelfinavir, NVP, ritonavir, stavudine, and TDF, sufficient numbers of first trimester exposures have been monitored to detect at least a two-fold increase in risk of overall birth defects. No such increases have been detected to date. For lamivudine and ZDV, sufficient numbers of first trimester exposures have been monitored to detect a 1.5-fold increase in risk of overall birth defects and a two-fold increase in risk of birth defects in the more common classes: cardiovascular and genitourinary systems. No such increases have been detected with the exception of hypospadias following first trimester exposure to ZDV [26].

Table 2 provides a summary of first and second/third trimester exposures to each ARV alone or in combination and lists the proportion of birth defects reported for each of the exposures. With respect to TDF, the APR recorded a congenital anomaly prevalence of 2.3% (95% CI 1.3–3.9) in 606 live births following first trimester TDF exposure and 1.5% (95% CI 0.5–3.4) in a further 336 live births with initial TDF exposure during the second/third trimesters, with no specific pattern of anomalies reported [26]. The congenital anomaly prevalence following first trimester FTC exposure was 3.2% (95% CI 1.4–6.2) in 252 live births, and the prevalence following initial FTC exposure during second/ third trimesters was 1.5% (95% CI 0.2–5.3) in 134 live births. These prevalences are similar to those reported for other ARVs. In animal studies, perinatal exposure to EFV was associated with central nervous system (CNS) abnormalities in 3 out of 20 infant cynomolgus macaques [27]. There have been retrospective reports, predominantly in infants from the USA, of increased rates of congenital abnormalities following in utero EFV exposure [26, 28]. Prospective reporting to the APR includes defects in 13 out of 407 infants with first trimester exposure to EFV, with a single case of myelomeningocele, the first prospective report of a neural tube defect following exposure to EFV. The APR also received a first case of anophthalmia, a defect reported in a study in monkeys; however, the case also included severe oblique facial clefts and amniotic banding, a known association with anophthalmia [26]. Continued prospective surveillance for women receiving ARVs in pregnancy, reporting both the immediate and long-term health outcomes for their infants, is required to fully evaluate the association between individual ARVs and congenital anomalies.

NRTIs and mitochondria In addition to concerns of PTD and congenital anomalies in ARV-exposed but uninfected infants, NRTIs such as ZDV have been associated with mitochondrial toxicity in vitro, in animal models, and in NRTI-exposed adults, children and infants, the latter having been recently reviewed [22]. Inhibition of DNA polymerase g is one of the mechanisms by which NRTIs cause mitochondrial toxicity [22,29, 30]. In vitro studies of the effects of increasing exposure to NRTIs on mitochondrial DNA (mtDNA) and mitochondrial function in a variety of human cell types have demonstrated that the potential for mitochondrial toxicity of NRTIs is ddI4stavudine (d4T)4ZDV43TC 5 abacavir (ABC) 5 TDF [31]. Studies in both human and monkey infants perinatally exposed to NRTIs have demonstrated abnormalities in mitochondrial structure (EM) and mtDNA depletion in a wide variety of tissue types [32–35]. The long-term clinical implications remain uncertain, although, in uninfected children exposed perinatally to ZDV, mtDNA depletion in peripheral blood mononuclear cells persists until 2 years of age [36]. Cohort studies of children perinatally exposed to ARVs offer conflicting data. Following reports of mitochondrial dysfunction after perinatal NRTI exposure, prospective analysis of over 2600 children from a French cohort showed an incidence of neurological/mitochondrial disease of 0.26%, compared with a population incidence of 0.01% [22,37,38]. However, initial retrospective analyses of other large US and European infant cohorts did not show an increase in ARV-associated mitochondrial disease [8,39]. While transient hyperlactaemia is well recognized in infants following perinatal NRTI exposure, the majority do not exhibit clinical mitochondrial disease, although it is important to remember that mtDNA mutations accumulate over time and mtDNA repair mechanisms are more limited than nuclear DNA repair mechanisms [22,40,41]. The European Medicines Agency has requested that pharmaceutical companies in Europe investigate the possible effects of in utero NRTI exposure on mitochondrial function. The Mitochondrial Toxicity in Children (MITOC) study is prospectively enrolling a large cohort of children.

TDF and mitochondria: in vitro data TDF, an NRTI, is associated with minimal inhibition of DNA polymerase g [30]. In vitro exposure to extremely high doses of TDF in a variety of human cell types showed no reduction in mtDNA, no effect on cellular expression of cytochrome c oxidase (COX) II or COX IV mitochondrial respiratory chain proteins and an increase in cellular lactic

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Table 2 Number of birth defects* by trimester of earliest exposure to each drug-prospective antiretroviral pregnancy Earliest trimester of exposure First trimester Defects/live births Proportion of defects reported with an exposure to any ARTz 126/4329 Proportion of defects reported with an exposure to:z,§ Any NRTI-containing regimen 124/4200 Any abacavir regimen 18/578 Any didanosine regimenz 16/362 Any emtricitabine regimen 8/252 Any entecavir regimen 0/2 Any lamivudine regimen 91/3089 Any stavudine regimen 19/696 k 0/1 Any telbivudine regimen Any zalcitabine regimen 2/40 Any zidovudine regimen 94/3068 Any NtRTI-containing regimen 14/636 k Any adefovir dipivoxil regimen 0/30 Any tenofovir regimen 14/606 Any NNRTI-containing regimen 30/1110 Any delavirdine regimen 0/11 13/407 Any efavirenz regimen** Any nevirapine regimen 18/785 Any PI-containing regimen 65/2156 Any amprenavir regimen 1/28 Any atazanavir sulphate regimen 5/246 Any darunavir regimen 2/18 Any fosamprenavir calcium regimen 1/57 Any indinavir regimen 6/275 Any lopinavir regimen 8/420 Any nelfinavir regimen 37/1066 Any ritonavir regimen 18/783 Any saquinavir regimen 6/148 Any tipranavir regimen 0/3 Any EI-containing regimen 0/14 Any enfuvirtide regimen 0/14 Any maraviroc regimen 0/0 Any InSTI-containing regimen 0/3 Any raltegravir regimen 0/3

Second/third trimester Prevalence (95% CI)w

Defects/live births

Prevalence (95% CI)w

145/5618

3.1% (1.9%, 4.9%) 4.4% (2.5%, 7.1%) 3.2% (1.4%, 6.2%) 2.9% (2.4%, 3.6%) 2.7% (1.7%, 4.2%)

3.1% (2.5%, 3.7%)

2.3% (1.3%, 3.9%)

3.2% (1.7%, 5.4%) 2.3% (1.4%, 3.6%)

2.0% (0.7%, 4.7%)

2.2% 1.9% 3.5% 2.3%

(0.8%, (0.8%, (2.5%, (1.4%,

4.7%) 3.7%) 4.8%) 3.6%)

147/5679 25/829 5/255 2/134 0/0 121/4631 6/190 0/0 0/12 161/6063 5/335 0/0 5/336 28/1143 0/2 2/37 27/1146 85/3217 0/9 3/116 0/8 0/22 3/160 23/963 61/2167 31/1184 8/191 0/1 0/7 0/6 0/1 0/3 0/3

3.0% (2.0%, 4.4%) 2.0% (0.6%, 4.5%) 1.5% (0.2%, 5.3%) 2.6% (2.2%, 3.1%) 3.2% (1.2%, 6.8%)

2.7% (2.3%, 3.1%)

1.5% (0.5%, 3.4%)

5.4% (0.7%, 18.2%) 2.4% (1.6%, 3.4%)

2.6% (0.5%, 7.4%)

1.9% 2.4% 2.8% 2.6%

(0.4%, (1.5%, (2.2%, (1.8%,

5.4%) 3.6%) 3.6%) 3.7%)

Individuals may appear in more than one category, as exposures are not mutually exclusive. *Defects meeting the Centers for Disease Control and Prevention (CDC) criteria only. Excludes reported defects in abortions o20 weeks. w Prevalence and 95% confidence intervals (CIs) are reported for first trimester exposures to drugs that have a denominator of 200 or greater. z Proportion of defects calculated by dividing the number of defects meeting the CDC criteria by the number of live births reported. § There were 56 outcomes with an exposure to a medication occurring in an unknown trimester. These cases are excluded where trimester is unknown; however, they may be represented in a known trimester for another medication. z The Registry notes the high frequency of defects after first trimester exposure to didanosine compared with second/third trimester exposures. All defects were reviewed and no pattern was discovered. k For treatment of hepatitis B virus. **The 13 infants with defects reported with first trimester exposure to efavirenz showed: (1) polydactyly, (2) hydronephrosis, (3) bilateral hip dislocation and umbilical hernia, (4) bilateral hip dislocation, (5) urinary obstruction, duplicated right collecting system with obstructed upper pole moiety, possibly associated with vesicoureteral reflux, (6) polydactyly, (7) long bone malformation, (8) sacral aplasia myelomeningocele and hydrocephalus with foetal alcohol syndrome, (9) shortening of right leg, (10) cutis aplasia (scalp), (11) hip dysplasia and pulmonary stenosis, (12) bilateral facial cleft, anophthalmia and amniotic band, and (13) postaxial polydactyly, both hands. For each exposure category (drug classification), counts represent the number of outcomes with at least one exposure in that classification, although other classes of antiretroviral therapy (ART) could have been included in the regimen. Additionally, any individual ART may have been used in combination with other ARTs, and therefore the counts represent the number of exposures to the individual ART contained in the regimen. Hence, counts are not mutually exclusive across classifications or individual ART. Data are not included for one case with birth defects with an unknown trimester of exposure. EI, entry inhibitor; InSTI, Intergrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NtRTI, nonnucleotide reverse transcriptase inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Registry cases with follow-up data closed on 31 January 2008 [26]

acid that was o10% of that seen following exposure to ZDV [30]. In animal models, TDF exposure was not associated with a reduction in mtDNA content or enzyme function [42]. Selecting ARVs with a lower propensity for

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mitochondrial toxicity for use in prevention of MTCT would be theoretically advantageous, provided that there was no increase in other toxicities for the mother or her infant.

402 C Foster et al.

Tenofovir in MTCT: animal data Tenofovir in a rhesus monkey model rapidly crossed the placenta, achieving peak concentrations in the foetus at 1 to 3 h following maternal administration [43]. TDF was administered subcutaneously at a dose of 30 mg/kg to gravid macaques during the second and third trimesters and their offspring received the same dose subcutaneously for 9 months. These doses provided exposures to TDF [based on the areas under the concentration curves (AUCs)] estimated to be 30–40-fold higher than those for a 300 mg TDF tablet in an adult human [43]. Exposure to high-dose TDF led to bone-related toxicity and severe growth restriction in approximately 25% of the monkey infants [43]. A subsequent study using a similar maternal tenofovir dose, but with no postnatal tenofovir exposure, showed a significant reduction in circulating insulin-like growth factor and a small reduction in overall body weight and crown-rump lengths and bone porosity in newborn infant rhesus monkeys compared with age-matched controls [44]. However, when infant macaques were given a range of tenofovir doses (4–30 mg/kg/day subcutaneously) for short periods of time (1 day–12 weeks) or 10 mg/kg/day subcutaneously for over 5 years with no maternal exposure in utero, no adverse events were seen in the infant macaques. Follow-up ranged from 2 months to 5 1 years and included urinalysis, serum biochemistry, in vivo fluorochrome bone labelling, dual-energy X-ray absorptiometry (DEXA) scans, bone biopsies and histology on euthanized animals. Thus, it appeared that the postnatal use of a short course of tenofovir at a wide dose range and the longer term use of tenofovir at 10 mg/kg/day was safe in this animal model [45]. In addition, one macaque, on TDF since birth, has now had three offspring, all of whom appeared healthy up to 5 years of age [46]. Additionally, lower doses of tenofovir have been shown to protect newborn macaques against oral simian immunodeficiency virus (SIV) infection. Thirteen newborn macaques were inoculated orally with virulent SIV. Administration of two doses of tenofovir (4 mg/kg subcutaneously) prevented infection in five out of eight infant macaques compared with zero out of four infant macaques given placebo [47].

TDF or TDF/FTC in pregnancy and for prevention of MTCT: data in humans Use of TDF or TDF/FTC in humans in treatment strategies for the prevention of MTCT has recently received increased attention. Both TDF and FTC have relatively long plasma half-lives: approximately 17 h for TDF and 8 h for FTC [48–51]. Tenofovir rapidly crosses the placenta in pregnant

women on HAART, achieving a maternal:cord blood tenofovir ratio of approximately 0.65–1 [52–54]. Administration of a single 600 mg dose of TDF in HIV-1-infected pregnant women after 34 weeks’ gestation led to maternal tenofovir concentrations that were similar to those in HIVinfected patients receiving long-term therapy with TDF 300 mg once daily, with the median cord blood tenofovir concentration being 65% of the median maternal blood concentration [54]. The potential role of TDF plus FTC in combination with SD-NVP and short-course ZDV has recently been explored in clinical trials for the prevention of MTCT. The addition of single-dose TDF/FTC to SD-NVP, as previously discussed, significantly reduced the development of NNRTI resistance, but did not further reduce the rate of HIV-1 transmission [18]. A similar strategy was studied in the TEmAA French National Agency for AIDS Research (ANRS) 12109 Trial [55,56]. Thirty-eight HIV-positive pregnant women received short-course ZDV, SD-NVP and two doses of TDF/FTC at the onset of labour, followed by once daily TDF/FTC for 7 days postpartum. All infants received one dose of NVP and 7 days of ZDV. Tenofovir plasma levels at delivery in maternal and cord blood were comparable to steady-state plasma levels in adults on TDF-based HAART. Two infants had detectable virus at 3 days postpartum, suggesting in utero rather than perinatal transmission [55, 56]. No genotypic resistance to NVP, TDF, ZDV or FTC was reported in the mothers or the two infected infants [55]. In a much larger study, 397 Zambian women were randomized to receive standard of care (ZDV from 32 weeks’ gestation plus SD-NVP) with or without an additional single dose of TDF/FTC at the onset of labour [18]. Women who received TDF/FTC in addition to standard care were less likely than controls to have an NNRTI mutation (detected at a subpopulation level of 20%) at 2 weeks postpartum [relative risk (RR) 0.27; 95% CI 0.11–0.66; P 5 0.002] or at 6 weeks postpartum (RR 0.47; 95% CI 0.29–0.76; P 5 0.002). No resistance mutations associated with TDF, FTC or ZDV were detected. The overall rate of perinatal HIV transmission at 6 weeks was similar in the intervention group (10 of 180; 5.6%) and the control group (14 of 175; 8.0%; P 5 0.403), although the study was not powered to assess the impact of the intervention on rates of MTCT. There were no differences in serious adverse events (the most common being anaemia) in mothers or infants between the two groups, although toxicity data were limited [18]. While the evidence for a reduction in NNRTI resistance produced by the addition of SD-TDF/FTC to SD-NVP and perinatal ZDV appears compelling, the question of the possible benefits of SD-TDF/FTC in regions where NVP alone is available remains unanswered. The simplicity of such a strategy has exciting potential and requires further

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investigations in resource-poor settings in well-powered randomized controlled trials with more extensive infant follow-up for any evidence of toxicity. In well-resourced settings, perinatal single-dose TDF is occasionally being used in addition to HAART for women delivering with detectable viral loads, particularly in cases of premature labour, where the infant is unlikely to tolerate oral ARVs. In this setting, a single maternal 600 mg dose of tenofovir can rapidly reach the infant via placental transfer [54]. The use of this simple maternal oral treatment strategy warrants further investigation, especially for premature infants, where ZDV remains the only licensed ARV for intravenous use.

The way forward Taken together, despite small numbers, these data are reassuring for the increasing numbers of HIV-1-uninfected infants with varying degrees of perinatal exposure to TDF or TDF-containing HAART. In well-resourced settings, rates of MTCT are so low that it is inherently difficult to demonstrate an additional benefit of a single intervention in further reducing MTCT, and this would require extremely large numbers in randomized controlled trials. However, as only a minority of women have access to HAART, further exploration of simple, safe, inexpensive and effective interventions in resource-limited settings is important. Additional data on safety and the potential reduction of MTCT with the addition of SD-TDF to SD-NVP, both for mothers and for their infants, are required where ZDV/HAART is not accessible. As an increasing number of women receiving TDF-based HAART choose to conceive, increasing numbers of HIVuninfected infants will be exposed to tenofovir during early foetal life. While evidence from the APR is encouraging, further safety data, including long-term follow-up after in utero exposure to TDF and all other ARVs, are required. Appropriate studies present several technical challenges. Assessment of bone mineralization effects by DEXA scanning is limited by a lack of normative data in African racial groups, expense, accessibility, requires a co-operative child usually aged 5 years or older, and has not been established as a surrogate marker of TDF-associated bone toxicity. Renal tubular dysfunction associated with TDFbased HAART is recognized in HIV-infected adult and paediatric populations [57,58]. Assessment of nephrotoxicity using calcium/phosphate creatinine ratios or urine proteinuria in infants exposed to TDF in utero is not standardized in this setting and longitudinal studies are required to address these issues. In view of the concerns around adverse pregnancy outcomes associated with PI-based HAART, non-PI-based

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combination therapy should be reconsidered [3,4,20,23,24] NVP is contraindicated because of increased toxicity in pregnant women with CD4 counts 4250 cells/mL [1,3,4, 19,26,59–62]. Because of the potential risk of neural tube defects with EFV exposure [1,3,4,62–64], current EU and US labelling state that Atripla, a single coformulated tablet of EFV, FTC and TDF, should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. Mothers on Atripla should be instructed not to breast-feed [65,66]. Before Atripla can be widely used in pregnancy or for PMTCT, additional data are required on: the placental transfer of TDF, FTC and EFV; the half-lives of the drugs in the full-term and preterm neonate; infant drug exposure during breast-feeding; the risk of viral resistance when HIV is transmitted; and potential toxicity in both mothers and their infants. An interesting study, ANRS 12200, recently outlined at the Dominic Dormont conference in Paris, plans to assess the safety and efficacy of Atripla beginning at 20 weeks’ gestation and continued at least until breast-feeding cessation [67].

Conclusions The transmission of HIV-1 from mother to child is preventable. However, most pregnant women world-wide do not have access to HAART, so SD-NVP remains a very important strategy in such settings, but does have limitations. The potential benefits of adding TDF or TDF/FTC to reduce NNRTI mutations associated with SDNVP and to further reduce rates of MTCT in this setting are exciting and require further exploration. While early data on outcomes for infants following perinatal TDF exposure are encouraging, prospective follow-up of HIV-1-uninfected children exposed to TDF is required. ZDV has played a very important role in the prevention of MTCT. Investigation of newer, less toxic ARV agents is required if we are to improve outcomes for infants born to HIV-1infected women in the future.

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