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Treatment switches during pregnancy among HIV-positive women on antiretroviral therapy at conception

Huntington, Susie E.a,b; Bansi, Loveleen K.a; Thorne, Claireb; Anderson, Janec; Newell, Marie-Louiseb,d; Taylor, Graham P.e; Pillay, Deenana,f; Hill, Teresaa; Tookey, Pat A.b; Sabin, Caroline A.aon behalf of the UK Collaborative HIV Cohort (UK CHIC) Study and the National Study of HIV in Pregnancy and Childhood (NSHPC)

doi: 10.1097/QAD.0b013e32834982af
EPIDEMIOLOGY AND SOCIAL
Free

Objectives: To describe antiretroviral therapy (ART) use and clinical status, at start of and during pregnancy, for HIV-positive women receiving ART at conception, including the proportion conceiving on drugs (efavirenz and didanosine) not recommended for use in early pregnancy.

Methods: Women with a pregnancy resulting in a live-birth after 1995 (n = 1537) were identified in an observational cohort of patients receiving HIV care at 12 clinics in the UK by matching records with national pregnancy data. Treatment and clinical data were analysed for 375 women conceiving on ART, including logistic regression to identify factors associated with changing regimen during pregnancy.

Results: Of the 375 women on ART, 39 (10%) conceived on dual therapy, 306 (82%) on triple therapy and 30 (8%) on more than three drugs. In total, 116 (31%) women conceived on a regimen containing efavirenz or didanosine (69 efavirenz, 54 didanosine, seven both). Overall, 38% (143) changed regimen during pregnancy, of whom 44% (n = 51) had a detectable viral load around that time. Detectable viral load was associated with increased risk of regimen change [adjusted odds ratio 2.97, 95% confidence interval (CI) (1.70–5.19)], while women on efavirenz at conception were three times more likely to switch than women on other drugs [3.40, (1.84–6.25)]. Regimen switching was also associated with year at conception [0.89, (0.83–0.96)].

Conclusion: These findings reinforce the need for careful consideration of ART use among women planning or likely to have a pregnancy in order to reduce viral load before pregnancy and avoid drugs not recommended for early antenatal use.

aUCL Medical School, Royal Free Campus

bMRC Centre of Epidemiology for Child Health, UCL Institute of Child Health, University College London

cHomerton University Hospital NHS Foundation Trust, London, UK

dAfrica Centre for Health and Population Studies, University of KwaZulu-Natal, Durban, South Africa

eImperial College Healthcare NHS Trust, St Mary's Hospital

fHealth Protection Agency, Centre for Infections, London, UK.

Correspondence to Mrs Susie Huntington, Research Department of Infection and Population Health, UCL Medical School, Royal Free Campus, Rowland Hill Street, London NW3 2PF, UK. Tel: +44 20 7794 0500 x34684; fax: +44 20 7794 1224; e-mail: susan.huntington.09@ucl.ac.uk

Received 17 March, 2011

Revised 26 May, 2011

Accepted 3 June, 2011

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Introduction

With the advent of reliable therapy to delay disease progression and prevent mother-to-child transmission (MTCT), an increasing number of women known to be HIV-positive are having children [1]. Currently more than 1200 deliveries are reported annually in this group in the UK, and around 70% of these are among women diagnosed before pregnancy; half of whom are on combination antiretroviral therapy (ART) when they conceive [2].

Unique considerations apply to antenatal ART use reflecting the dual goals of preventing transmission and delaying maternal disease progression, while considering the developing foetus. All HIV-positive pregnant women are recommended ART to prevent MTCT as well as for their own health if required [3]. UK guidelines recommend that women conceiving on therapy continue on the regimen, unless it is failing, and those not yet on therapy initiate ART after their first trimester, the period of greatest concern for teratogenicity [3].

Efavirenz together with a nucleoside backbone is the recommended first-line ART regimen in the UK [4] but current guidelines recommend that women likely to conceive avoid efavirenz due to safety concerns [3]. Limited animal study data and case reports of neural tube defects in infants exposed to efavirenz in the first trimester form the basis for these concerns [5–7]. Birth defects, including neural tube defects, were observed in 2.8% live-births with first trimester exposure, as reported to the Antiretroviral Pregnancy Registry [8]. However, observational cohorts indicate that the prevalence of all congenital abnormalities is not significantly higher among infants exposed to efavirenz in utero than among those exposed to other antiretrovirals [9–11]. There are insufficient data to exclude a small increase in the risk of specific malformations and in the UK it is recommended that women planning a pregnancy use nevirapine-based regimens (if they have CD4 cell count <250 cells/μl) or boosted protease inhibitor-based regimens [4].

Didanosine, no longer widely used, may be associated with a higher incidence of birth defects in exposed infants compared with commonly used antiretrovirals; defects occurred in 4.7% live-births with first trimester exposure, although no pattern of defects was seen [8]. Although UK guidelines recommend that women who may conceive avoid using efavirenz or didanosine [3], they recommend that if women conceive on these drugs, they continue this regimen, unless it is failing [3]. The rationale being that if a woman conceives on efavirenz and switches treatment, the foetus is unlikely to avoid exposure during the period of initial neural development because the drug has a long half-life and there is normally some delay before presenting for antenatal care [3].

Through data linkage of two observational HIV studies, we identified women receiving ART at conception of their first reported pregnancy. Our objectives were to describe the virological, immunological and treatment characteristics of these women, including the proportion using efavirenz or didanosine at conception, and to investigate the frequency of and risk factors associated with antenatal ART switching.

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Methods

Data collection

The UK Collaborative HIV Cohort (UK CHIC) is an observational study collating HIV-related clinical data from many of the UK's largest HIV clinical centres (see Acknowledgements). UK CHIC includes demographic data, dates and results of CD4 cell count/viral load assessments, and ART start and stop dates; data on pregnancy status are not reported. UK CHIC includes approximately one-third of HIV-positive individuals receiving care in the UK over this period and is described elsewhere [12].

Through the National Study of HIV in Pregnancy and Childhood (NSHPC), data on HIV-positive women diagnosed prior to or during antenatal care are collected from every maternity unit in the UK/Ireland through confidential quarterly active reporting. Data collected include demographic details, timing of maternal diagnosis, expected delivery date (EDD), delivery date, pregnancy outcome, CD4 cell count/viral load results and dates during pregnancy and ART use at conception and during pregnancy. Further details are available at www.nshpc.ucl.ac.uk, and elsewhere [1].

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Dataset linkage

Women in UK CHIC with a pregnancy were identified by matching records to the NSHPC dataset. Both datasets are pseudonymized. Initially, records in NSHPC were linked to records in UK CHIC using maternal date-of-birth (DOB; Fig. 1) (a). Other data fields were then used to confirm matches between linked records. Records with an exact CD4 cell date match were confirmed as a match if they also had either CD4 cell count (±10 cells/μl) match on that date, attended the same hospital or had identical HIV-diagnosis dates (b). The same criteria were then used to identify matches between records with matching CD4 cell date ±30 days (c). Linked records with no matching CD4 cell dates ±30 days but with matching drug start/stop dates were then confirmed as a match (d). Further matches were manually identified from the remaining linked records using drug start/stop dates, date of HIV diagnosis, country of birth and viral load dates (e). Mortimer Market Centre, which provides HIV services, is closely located to University College Hospital, which provides maternity care; during the matching process, these were classed as the same site.

Fig. 1

Fig. 1

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Study population

In total, 1710 records for women seen for HIV care between 1996 and mid-2009 were matched to a NSHPC record. Matched records were representative of all records in the NSHPC dataset, with respect to factors including ethnicity, mode of HIV acquisition and clinical status. Further records (n = 144) were linked using DOB and site but could not be confirmed as a match due to missing/discrepant diagnosis date or CD4 cell data. Pregnancies resulting in termination (n = 61), miscarriage (n = 92) or stillbirth (n = 17) and ectopic pregnancies (n = 2) were excluded as well as one woman who left the UK before delivery. Of the 1537 women with a pregnancy resulting in a live-birth, 720 (47%) received HIV-related care prior to their first reported pregnancy (typically, the first pregnancy since HIV-diagnosis and/or arrival in the UK); 375 (24%) women were on ART at time of conception of their first reported pregnancy, representing 52% of those receiving clinical care. This group of 375 women forms the study population for the analyses.

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Variables and definitions

Pregnancy duration varied and actual delivery date was up to 98 days before EDD; therefore, estimated date of conception was calculated as 266 days before EDD (normally calculated using ultrasound scan) or before actual delivery date if EDD was missing. Data from UK CHIC were used in the analysis; wherein demographic data or HIV-diagnosis date was missing, NSHPC data were used. Viral load was defined as undetectable if it was below the detection threshold of the assay used at the time, typically 50 copies/ml.

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Data analysis

A regimen switch was defined as a discontinuation or introduction of at least one ART drug during pregnancy. The Kaplan–Meier method was used to estimate median time to first regimen switch. Fisher's exact test was used to assess changes in drug use over time. Univariate and multivariable logistic regression were used to identify factors associated with any regimen switch; factors considered included type of ART at conception, viral load at conception and calendar year at conception. Data analysis was undertaken using SAS 9 (SAS Institute Inc., Cary, North Carolina, USA).

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Results

Characterizing women on antiretroviral therapy at conception

Almost three-quarters of the 375 women on ART at conception were black-African and the majority were infected heterosexually (Table 1). At conception, median time since HIV-diagnosis was nearly 4 years; half were severely immunosuppressed (CD4 cell count <200 cells/μl) around the time of diagnosis (<90 days before diagnosis in the UK and before starting ART; Table 1). Median time since starting ART was 2.4 years and one-fifth (n = 81, 22%) had initiated ART less than 12 months prior to conception. Ninety-three percent of women had CD4 cell count less than 350 cells/μl when they started ART (Table 1).

Table 1

Table 1

By the time of conception, median CD4 cell count had substantially increased and 74% of women had achieved undetectable viral load (Table 2). Median viral load among the 27% of women with detectable levels at conception was 900 copies/ml [interquartile range (IQR) 134–5914 copies/ml]. The majority of women with CD4 cell count less than 200 cells/μl at conception (n = 44) had also been severely immunosuppressed at diagnosis (81%, 21/26, wherein data were available), which occurred a median of 16 months before conception in this group.

Table 2

Table 2

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Antiretroviral therapy use

The majority of women were receiving a combination of three ART drugs (n = 306, 82%) and nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens predominated (Table 2). Of the 39 women on fewer than three drugs, 38% (n = 15) conceived after 2005. One-third of women (132/375, 35%) were using a regimen containing nevirapine; 18% (n = 69) were using efavirenz and 14% (n = 54) didanosine, including seven women (2%) using efavirenz and didanosine. Of those using efavirenz, 43% (n = 30) were on their first regimen, 25% (n = 7) had efavirenz in their first regimen but had changed another component of the regimen and 32% (n = 22) had switched to using efavirenz. Of women on didanosine, 19% (n = 10) were on their first regimen. Overall, at conception women had been on their current regimen for a median of just under 1 year. Around half those conceiving on efavirenz or didanosine had started the regimen within the previous year [37/69 (54%) and 27/54 (50%), respectively].

The percentage of women using either didanosine or efavirenz at time of conception was 20% (11/55) in 1996–2000, 37% (62/166) in 2001–2005 and 28% (43/153) in 2006–2009. Since 2001, use of didanosine fell, from 30% (seven of 23) to 0 in 2009 [5% (two of 40) in 2008; P = 0.07)], as did use of efavirenz, from 30% (seven of 23) in 2001 to 13% (two of 15) in 2009 (P = 0.7). Four women conceived on darunavir (in 2008–2009); two were also on etravirine – none switched treatment during pregnancy. Of the 21 women who conceived on atazanavir, six (29%) discontinued its use [half (three of six) with undetectable viral load around the time of switch]; four switched to zidovudine, one to boosted saquinavir (a protease inhibitor) and one remained on a boosted protease inhibitor. No women conceived on tipranavir.

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Antiretroviral therapy switching

More than one-third (n = 143, 38%) of women switched regimen during pregnancy, including 22 women who interrupted treatment. Regimen switches occurred during the first, second and third trimesters [62% (n = 98), 29% (n = 41) and 9% (n = 13), respectively]. Median time to switch was 2.1 months (IQR 1.1–4.3 months) from time of conception. Median CD4 cell count in the 90 days before regimen change was 290 cells/μl (IQR 186–460 cells/μl). Median viral load around the time of changing was 50 copies/ml (IQR 50–6047 copies/ml) and 56% (65/116) had an undetectable viral load at this time.

Fifty-nine percent (41/69) of those who conceived on efavirenz changed regimen during pregnancy compared to 50% (27/54) of women on didanosine and 24% (32/132) of those on nevirapine. Most regimen changes among women on efavirenz were discontinuations of this drug (85%, 35/41), higher than for didanosine (66%, 18/27 discontinued this drug) or nevirapine (53%, 17/32). Among women discontinuing efavirenz, 17 (49%) stopped within 6 weeks of conception, nine (26%) after 6–12 weeks and nine (26%) after 12 weeks, the latest at 21 weeks. In contrast, among women discontinuing didanosine, four (22%), five (28%) and nine (50%) stopped in these three periods, respectively. There were also differences with respect to virological status in early pregnancy, with 25% (eight of 32) of women switching from efavirenz having detectable viral load around the time of conception, compared with 56% (10/18) of those switching from didanosine.

Among women discontinuing efavirenz, four switched to nevirapine; 13 started a protease inhibitor [ritonavir (n = 10), saquinavir (n = 1) or nelfinavir (n = 1)]; two started tenofovir and 11 zidovudine (five monotherapy). The majority remained on at least one NRTI (22/35, 63%), two remained on just NRTIs and two started additional NRTIs. Among those discontinuing didanosine, the most common regimen change was to an alternative NRTI [zidovudine (n = 10), abacavir (n = 1), emtricitabine (n = 1) or stavudine (n = 1)]; one woman started efavirenz and two restarted didanosine in their second trimester. One woman who conceived on didanosine and efavirenz interrupted ART, restarting after delivery.

Conception on an efavirenz-containing regimen was the strongest risk factor for treatment switch identified in multivariable logistic regression. Adjusting for viral load around time of conception and calendar year, women who conceived on efavirenz were more likely to change regimen during pregnancy compared with women on other drugs [adjusted odds ratio 3.40 (95% CI 1.84–6.25) P < 0.001]. Women were less likely to switch treatment in later years even after adjusting for ART use and viral load at conception [0.89 (0.83–0.96) P = 0.002] (Table 3). Repeating this logistic regression using drug discontinuation as the outcome produced similar results (data not shown).

Table 3

Table 3

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Viral load

Among the 27% (n = 84) with detectable viral load at start of pregnancy, 51% (36/70) achieved undetectable levels by their third trimester [52% (23/44) of those who switched regimen and 50% (13/26) of those who did not]. Nearly two-thirds of those with detectable viral load at start of pregnancy had been on ART for at least 1 year (63%, n = 53) with 27% (n = 23) on ART for less than 6 months; 43% (n = 36) had been on their current regimen for less than 6 months. Thirty-four women had detectable viral load at conception and delivery, of whom 13 (38%) did not switch treatment during pregnancy [3.5% (13/375) of the overall group].

Overall, 82% (252/306) had viral load below the limit of detection in their third trimester; among the 54 women with detectable viral load, the median was 289 copies/ml (IQR 113–942 copies/ml).

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Transmission

HIV infection status was available for 340 infants. One child (0.3%, 95% CI 0.0–0.9%), born in 2007, was infected. In this case, the mother conceived on lamivudine and abacavir. Additional drugs were included in her regimen but viral load was not suppressed by delivery.

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Discussion

In our study, HIV-positive women conceiving on ART had been diagnosed for a median of 3.7 years and treated on average for nearly 2.5 years. At conception, median CD4 cell count was 390 cells/μl indicating that most women were in good health, despite many having CD4 cell count less than 200 cells/μl at diagnosis. However, 14% started pregnancy with CD4 cell count less than 200 cells/μl, similar to results from other European studies [13]. The transmission rate was low, as would be expected among women conceiving on ART [14].

Most women (78%) had received ART for over a year at conception. NNRTI-based regimens predominated, with efavirenz taken in one-third of these. Despite treatment guidelines recommending that women planning a pregnancy avoid efavirenz or didanosine, as they may increase risk of congenital abnormalities, almost one-third conceived while receiving one of these drugs. This is higher than the proportion reported from an Italian study, which reported that 17% of women conceiving on ART from 2002 to 2008 were receiving these drugs [15].

Treatment changes during pregnancy may be required due to a failing regimen, or toxicities, or may be prompted by safety concerns. Overall, 38% of women here switched regimens, the amount of switching decreasing over time. UK guidelines recommend that women conceiving on efavirenz continue this regimen, unless it is failing. Half the women conceiving on efavirenz here changed regimens, three-quarters in the first trimester, suggesting that the changes were prompted by safety concerns. This is supported by our finding that the probability of switching during pregnancy was 3.26 times greater among women on efavirenz compared with women on other antiretrovirals. In Italy, women conceiving on efavirenz were also more likely to change treatment than women conceiving on other ART drugs [16]. However, this reflects use of US guidelines, which differ from UK guidelines in stating that women conceiving on efavirenz should change to a suitable alternative if they present during the first trimester [5].

In our study, more than half the women switching from efavirenz did so after the first 6 weeks of pregnancy, not avoiding fetal exposure to the drug during the weeks when neural fusion occurs [11]. Of note, around 80% of women conceiving on efavirenz-based regimens had undetectable viral loads. Treatment interruptions and unnecessary switching of regimens that are effectively suppressing viral load should be avoided, particularly for women already on second-line therapy [4].

Around half the women conceiving on efavirenz had started this within the previous year, indicating that either they were not planning a pregnancy, did not discuss a planned pregnancy with their clinician or were planning a pregnancy but decided to use efavirenz despite possible risks. Efavirenz is an effective treatment, with health benefits over non-efavirenz regimens [17], particularly in settings with high levels of HIV/tuberculosis (TB) co-infection as it can be used in combination with rifampicin-based TB therapy. In Ivory Coast, where many women use efavirenz, a study comparing pregnancy outcomes between women conceiving on efavirenz (n = 213) and nevirapine (n = 131) observed no visible congenital malformations in either group [11]. Further risk–benefit analysis is needed regarding efavirenz use among women of childbearing age. Pregnancies not resulting in a live-birth were excluded from the analysis; however, it would be of interest, in future analyses, to investigate pregnancy outcome in relation to antenatal ART use and treatment switches.

Guidelines recommend that women planning a pregnancy are offered counselling prior to conception [3] and that HIV physicians should discuss pregnancy plans with women when making treatment decisions [4]. Our results reinforce this need, both to identify wherein increased adherence support or regimen change is required and to discuss switching regimen among women on efavirenz who do not wish to conceive on this drug. Any changes to treatment should be made swiftly to avoid switching during or close to the start of pregnancy. Given the probable high number of unplanned pregnancies in this population [16,18,19], it is important that clinicians prescribing ART consider that women of childbearing age may become pregnant and that appropriate contraception and advice is available.

Etravirine and darunavir are among a handful of drugs approved for use in the past 5 years. In our study, a small number of women conceived on these drugs in recent years and a larger number conceived on atazanavir, approved for use in 2003. It is likely that the number of women conceiving on these drugs will increase, although little is known about their safety profiles, and close monitoring of their pregnancy outcomes is thus crucial [8].

Viral load, the most important factor associated with vertical transmission, [14,20,21] was generally low around the time of conception. However, more than a quarter of women had nonsuppressed viral load at this time (although with low median viral load), similar to other reports [22]; this group included those who recently initiated ART (28% <6 months before), but 64% had been on ART for at least 1 year. This may be due to delays in treatment switching, previously reported as a concern in the UK [23]. More than half of those who did not switch regimen, despite having an unsuppressed viral load, attained viral suppression. Similarly, in a European study of women conceiving with unsuppressed viral load, 40% of the women not changing treatment attained viral suppression by delivery [22]. This may be due to improved adherence during pregnancy, as has been reported elsewhere [24,25], probably because women receive increased adherence support and/or because they have increased motivation to adhere. Women on a failing regimen should have resistance testing [4] and although changing regimen is not always necessary, half the women with detectable viral load at conception who did not switch treatment did not achieve viral suppression by delivery. This group might have benefited from switching treatment.

The median viral load among women with detectable levels in their third trimester was 289 copies/ml compared with 900 copies/ml among those with detectable levels at conception. Given more time, some of these women may have achieved undetectable levels. Although this group represent a small proportion of the overall group, they are at increased risk of MTCT, particularly as transmission is more likely to occur in the later stages of pregnancy [14,20,21]. During pregnancy, swift action is required to improve adherence or change a failing regimen among treated women with a detectable viral load, to attain viral suppression as quickly as possible.

Linkage between NSHPC and UK CHIC has allowed us to examine clinical data prior to as well as during pregnancy. However, several limitations of these datasets must be acknowledged. First, as with most large observational databases, both databases may contain missing/incorrect data, resulting in underlinkage. Second, although participants in UK CHIC are broadly representative of the UK HIV population, clinical practice in participating centres may differ from those at nonparticipating clinics. Third, UK CHIC does not collect information on reason for switching (or not switching) drugs, adherence or ART use prior to treatment at a centre participating in the study. Finally, NSHPC does not collect information on the date when women discovered they were pregnant; a date which is arguably of most relevance for any subsequent changes to care.

In summary, women planning a pregnancy should be encouraged to discuss this with their physician to facilitate optimal management, including avoidance of antiretrovirals for which there may be specific safety concerns. For women on treatment, the opportunity to achieve viral suppression before pregnancy and to maintain this throughout pregnancy should not be missed, given that MTCT can occur before, as well as during, the last trimester. Clinicians prescribing ART to women of childbearing age must consider that these patients might conceive. All treated HIV-positive women who become pregnant require a high level of clinical support, in particular those with unsuppressed viral load, who either require a change in regimen or support with their existing regimen. As the number of pregnancies among HIV-positive women on ART is increasing [1,22,26] and more women conceive on new ART drugs, continued surveillance and monitoring of pregnancy outcomes is vital.

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Acknowledgements

UK CHIC: UK Collaborative HIV Cohort.

Steering Committee includes the following members: Jonathan Ainsworth, Jane Anderson, Abdel Babiker, Loveleen Bansi, David Chadwick, Valerie Delpech, David Dunn, Martin Fisher, Brian Gazzard, Richard Gilson, Mark Gompels, Teresa Hill, Margaret Johnson, Clifford Leen, Mark Nelson, Chloe Orkin, Adrian Palfreeman, Andrew Phillips, Deenan Pillay, Frank Post, Caroline Sabin (PI), Memory Sachikonye, Achim Schwenk and John Walsh.

Central Co-ordination: UCL Medical School, Royal Free Campus, London (Loveleen Bansi, Teresa Hill, Susie Huntington, Andrew Phillips, Caroline Sabin); Medical Research Council Clinical Trials Unit (MRC CTU), London (David Dunn, Adam Glabay).

Participating centres are as follows: Barts and The London NHS Trust, London (C. Orkin, N. Garrett, J. Lynch, J. Hand, C. de Souza); Brighton and Sussex University Hospitals NHS Trust (M. Fisher, N. Perry, S. Tilbury, D. Churchill); Chelsea and Westminster Hospital NHS Trust, London (B. Gazzard, M. Nelson, M. Waxman, D. Asboe, S. Mandalia); Health Protection Agency – Centre for Infections London (HPA) (V. Delpech); Homerton University Hospital NHS Trust, London (J. Anderson, S. Munshi); King's College Hospital NHS Foundation Trust, London (H. Korat, J. Welch, M. Poulton, C. MacDonald, Z. Gleisner, L. Campbell); Mortimer Market Centre, London (R. Gilson, N. Brima, I. Williams); North Middlesex University Hospital NHS Trust, London (A. Schwenk, J. Ainsworth, C. Wood, S. Miller); Royal Free NHS Trust and UCL Medical School, London (M. Johnson, M. Youle, F. Lampe, C. Smith, H. Grabowska, C. Chaloner, D. Puradiredja); St. Mary's Hospital, London (J. Walsh, J. Weber, F. Ramzan, N. Mackie, A. Winston); The Lothian University Hospitals NHS Trust, Edinburgh (C. Leen, A. Wilson); North Bristol NHS Trust (M. Gompels, S. Allan); University of Leicester NHS Trust (A. Palfreeman, A. Moore); South Tees Hospitals NHS Foundation Trust (D. Chadwick, K. Wakeman).

National Study of HIV in Pregnancy and Childhood (NSHPC): We gratefully acknowledge the contribution of the midwives, obstetricians, genitourinary physicians, paediatricians, clinical nurse specialists and all other colleagues who report to the NSHPC through the British Paediatric Surveillance Unit of the Royal College of Paediatrics and Child Health, and the obstetric reporting scheme run under the auspices of the Royal College of Obstetricians and Gynaecologists. We thank Janet Masters who co-ordinates the study and manages the data and Icina Shakes for administrative support.

Ethics approval for NSHPC was renewed following review by the London Multi-Centre Research Ethics Committee in 2004 (MREC/04/2/009).

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Conflicts of interest

UK CHIC is funded by the Medical Research Council (MRC), UK (grants G00001999 and G0600337). NSHPC receives core funding from the Health Protection Agency (grant number GHP/003/013/003). Data are collated at the UCL Institute of Child Health which receives a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme. S.H. has a UCL Studentship, funded by the MRC, for postgraduate work. C.T. holds a Wellcome Trust Research Career Development Fellowship.

The views expressed in this article are those of the researchers and not necessarily those of the funders.

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Keywords:

antiretroviral agents; antiretroviral therapy; HIV; pregnancy; United Kingdom

© 2011 Lippincott Williams & Wilkins, Inc.