Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case–control study
Judd, Alia; Boyd, Katherine La; Stöhr, Wolfganga; Dunn, Davida; Butler, Karinab; Lyall, Hermionec; Sharland, Miked; Shingadia, Delanee; Riordan, Andrewf; Gibb, Di Ma
aMRC Clinical Trials Unit, London, UK
bOur Lady's Children's Hospital, Dublin, Ireland
cImperial College Healthcare NHS Trust, UK
dSt George's Healthcare Trust, UK
eGreat Ormond Street Hospital for Children NHS Trust, London, UK
fRoyal Liverpool Children's NHS Trust, Liverpool, UK.
Received 23 July, 2009
Revised 15 September, 2009
Accepted 18 September, 2009
Correspondence to Dr Ali Judd, MRC Clinical Trials Unit, 222 Euston Road, London NW1 2DA, UK. Tel: +44 20 7670 4830; e-mail: email@example.com
Objective: To investigate the association between tenofovir disoproxil fumarate (TDF) use and renal abnormality in a large cohort of HIV-1-infected children on antiretroviral therapy (ART).
Design: Nested case–control study.
Methods: Patients were from the Collaborative HIV Paediatric Study, a cohort of approximately 95% of HIV-1-infected children in the UK/Ireland. Serum (but not urine) biochemistry results for 2002–2008 were obtained for 456 ART-exposed children (2–18 years) seen at seven hospitals. Cases had either confirmed hypophosphataemia DAIDS grade at least 2 or estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 m2; three controls per case were matched by hospital. Conditional logistic regression identified risk factors for renal abnormality.
Results: Twenty of 456 (4.4%) had hypophosphataemia, and one had eGFR less than 60 ml/min per 1.73 m2. Ten of 20 (50%) cases versus 11 of 60 (18%) controls had taken TDF-containing ART for a median [interquartile range (IQR)] of 18 [17–20] months, as part of second-line or salvage therapy. The hypophosphataemia incidence rate was 4.3/100 person-years in the TDF group versus 0.9/100 person-years in those not exposed to TDF. In multivariable analysis, only TDF exposure in the previous 6 months was associated with hypophosphataemia [odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.45–16.0, P = 0.01]. In six of 10 children with hypophosphataemia and at least four subsequent phosphate measurements, phosphate values returned to normal when TDF was stopped; in four with three measures or less, values rose but remained subnormal.
Conclusions: Hypophosphataemia was uncommon (4%), but was associated with prolonged TDF use, and was generally reversible following TDF withdrawal. Findings highlight the importance of continuing to monitor longer-term renal function, in particular tubular function, especially in those taking TDF. Further studies assessing urine biochemistry measures which more accurately indicate renal tubular damage are required.
Although antiretroviral therapy (ART) has dramatically reduced morbidity and mortality in HIV-infected individuals, most ART drugs have some toxicity. Long-term toxicity is particularly important for children, who may be adversely affected during growth and development and are likely to take ART for longer than adults. A number of antiviral drugs have been linked to renal disease, including the nucleotide reverse transcriptase inhibitor (NRTI) tenofovir disoproxil fumarate (TDF) .
Anecdotal case reports in adults have described TDF-related severe tubular dysfunction, characterized by hypophosphataemia, elevated creatinine and/or glycosuria, and more rarely Fanconi syndrome, which may persist after TDF has been withdrawn [2–6]. However, randomized controlled trials (RCTs) comparing TDF-containing ART regimens to those not containing TDF in adults with normal baseline renal function have generally reported similar and good renal safety profiles in each group [7–10]. For example, Gallant et al.  compared TDF to either stavudine or zidovudine in two RCTs of ART-naive adult patients with normal or mildly impaired renal function, along with efavirenz and either lamivudine or emtricitabine; the proportion of patients who experienced confirmed abnormalities in serum creatinine or serum phosphate was less than 1% in both groups. Although patients in the TDF group had a small but statistically significant decrease in estimated glomerular filtration rate (eGFR) through 144 weeks (−2 ml/min per 1.73 m2, P < 0.05), this was not accompanied by clinically relevant renal disease or adverse events. Similarly, adult cohort studies have reported only small decreases in creatinine clearance and phosphate levels in those on TDF-containing regimens compared to alternative nucleoside analogues [11–14], and no increased risk of discontinuation of therapy or adverse events over periods of up to 2 years. In the large DART trial in Africa, participants with moderately impaired eGFR at baseline showed improvements during the first weeks after starting ART; most regimens included TDF, and only very small differences in eGFR were observed by regimen out to 4 years [12,15]. A low incidence of nephrotoxicity was observed in two other cohorts, and was associated with pre-existing comorbidities and older age [16,17].
Tenofovir disoproxil fumarate is not yet licensed for use in HIV-infected children less than 18 years of age, as results of a phase 2 trial are awaited. However, it is often used off-label in this population either as part of salvage therapy or for children co-infected with hepatitis B. As with adults, case reports highlight instances of proximal renal tubular dysfunction and other renal toxicities in a small number of children taking TDF [18–20]. Two studies which followed up ART-experienced children on TDF-containing regimens found no evidence of impaired glomerular or tubular renal function [21,22] but sample sizes were very small (27 and 18 children, respectively).
In a previous study we described the TDF dosing and patient characteristics in a cohort of HIV-1-infected children in the UK and Ireland . Results suggested reasonable levels of virological response considering those taking TDF had received many previous ART regimens. There was considerable underdosing and overdosing but few adverse events. In this study, we extend those analyses to investigate the association between use of TDF and risk of markers of renal abnormalities in the cohort, using a nested case–control approach.
Details of the Collaborative HIV Paediatric Study (CHIPS) have been published elsewhere [24,25]. In brief, infants born to HIV-infected women and children presenting in the UK and Ireland with HIV-1 infection are notified to the National Study of HIV in Pregnancy and Childhood, and followed up in CHIPS, which includes approximately 95% of HIV-1-infected children in the UK or Ireland. By the end of March 2008, 1460 children were enrolled in CHIPS, and 1130 were in active follow-up. Data for 2007/8 are subject to reporting delay.
Complete serum biochemistry results (including sodium, creatinine, potassium, albumin, urea, calcium and phosphate) from 2002 onwards (when TDF was licensed in adults) and laboratory-specific normal ranges were obtained for 456 ART-exposed children aged 2–17 years receiving direct care at the seven hospitals in CHIPS prescribing TDF most frequently. An additional 112 ART-exposed HIV-infected children aged 2–17 years were excluded as they were in shared care with another centre, and some of their biochemistry tests would have been analysed elsewhere. One hundred and thirty-one (29%) of the 456 had previously received TDF, and comprised 58% of the 224 children ever prescribed TDF in the whole CHIPS cohort. Biochemistry tests were performed approximately 3 monthly for children taking ART. Children under 2 years of age were excluded as TDF was not prescribed to this age group in the UK or Ireland and renal parameters show wide natural variation in infancy . Urine biochemistry tests were not routinely measured at any of the participating centres; only 56 urine phosphate and 345 urine creatinine levels were reported in 28 and 56 children, respectively. Urine samples were also not stored, so it was not possible to evaluate the role of urinary markers of renal tubular damage such as β-2 microglobulinuria between cases and controls.
Serum phosphate abnormalities were graded from 1 to 4 according to the Division of AIDS (DAIDS) adverse event tables [grade 1: ‘mild’, 2–14 years 0.97–1.13 mmol/l, ≥15 years 0.81-< lower limit normal (LLN); grade 2: ‘moderate’, 2–14 years 0.81–0.96 mmol/l, ≥15 years 0.65–0.80 mmol/l; grade 3: ‘severe’, 2–14 years 0.48–0.80 mmol/l, ≥15 years 0.32–0.64 mmol/l; grade 4: ‘potentially life-threatening’, 2–14 years <0.48 mmol/l, ≥15 years <0.32 mmol/l] . eGFR was calculated from serum creatinine levels using the Schwartz formula [CCr (ml/min per 1.73 m2) = (0.55 × height (cm))/SCr (mg/dl), where CCr = creatinine clearance and SCr, serum creatinine] and height, and classified according to guidelines from the National Kidney Foundation (‘mild reduction’ 60–89 ml/min per 1.73 m2; ‘moderate reduction’ 30–59 ml/min per 1.73 m2; ‘severe reduction’ 15–29 ml/min per 1.73 m2; ‘kidney failure’ <15 ml/min per 1.73 m2) . Children were categorized by whether they experienced a ‘moderate’ or greater event for each indicator of renal function (in other words serum phosphate DAIDS grade at least 2 or eGFR <60 ml/min per 1.73 m2).
Where an individual had multiple test results on the same day, the lowest value was selected for analysis. Additionally, results were only included if they were after a child had started three or four-drug highly active ART.
Trends over time in overall median serum phosphate and eGFR measures in children taking TDF were plotted for the period immediately before and after starting TDF. Individual graphs were produced for children experiencing a serum phosphate DAIDS grade at least 2 whilst taking TDF. Phosphate results for four children attending one of the seven hospitals and previously reported to have experienced a renal adverse event whilst taking TDF  were examined for evidence of abnormal serum phosphate values near the time of that reported adverse event.
For the case–control analysis, a case was defined as the first episode of confirmed (two results within 6 months) serum phosphate DAIDS grade at least 2 or moderate or greater reduction in eGFR (<60 ml/min per 1.73 m2). However, as only one child experienced a moderate or greater reduction in eGFR (see Results section), this indicator was not explored further. A sensitivity analysis defined cases as the first episode of confirmed serum phosphate less than the LLN of the normal range. Normal ranges varied by hospital, age, sex and calendar year, and the proportion of patients with a serum phosphate less than LLN was compared to the proportion with DAIDS grade at least 2.
Three randomly selected controls were matched to each case by hospital of attendance. They were censored at the date of the episode in the case, and were all in follow-up beyond this date. Controls could have mild reductions in phosphate (DAIDS grade 1) or eGFR (60–89 ml/min per 1.73 m2) or values outside the hospital's normal range on three or four-drug ART, prior to censoring. Socio-demographic characteristics, HIV-related indicators (CDC C events, CD4% and viral loads) and previous ART exposures were extracted from the CHIPS database.
Statistical analysis was performed using STATA version 10.0 (StataCorp LP, College Station, Texas, USA). Matched conditional logistic regression was undertaken to identify risk factors associated with the case definitions (serum phosphate DAIDS grade ≥2 or <LLN). Risk factors considered were sex; ethnicity; characteristics at the start of ART (naive at ART, CDC stage, CD4%, log HIV-1 RNA, grouped calendar year; serum phosphate DAIDS grade ≥2 prior to ART); years on ART; age and line of ART at event/censoring; ever hepatitis B virus (HBV) positive; and drug/class exposure in the previous 6 months (TDF, NNRTI, protease inhibitor). Significance tests were based on the likelihood ratio statistic. A regression model was built using a backwards stepwise approach, including factors found significant at P less than 0.10 in univariable analyses.
A second analysis used a Poisson approach to investigate the effect of current and cumulative exposure to TDF on risk of serum phosphate DAIDS grade at least 2, allowing time-updated variables, similar to a previous cohort analysis investigating ART drug class and risk of myocardial infarction in adults . Each patient's follow-up period was divided into consecutive 3-month periods, starting at the first biochemistry test result after January 2002 on ART. Each 3-month period was then assigned the appropriate exposure at the beginning of the period for age, calendar year and CDC stage, as well as the last recorded measure of CD4% and HIV-1 RNA in the prior 3-month period, if available. Other variables included in the model were the same as for the conditional logistic regression model. In addition, current or recent exposure to each NRTI was considered individually. Patients were censored at the date of the first confirmed serum phosphate at least 2, the last phosphate test result, or the end of CHIPS follow-up, whichever occurred first. Poisson regression models were used to explore the relationship between exposure and incidence of serum phosphate at least 2, and results were compared to the case–control approach.
One hundred and thirty-one (29%) of the 456 ART-exposed children included in this study had previously received TDF, for whom the median follow-up time from start of TDF was 2.1 years [interquartile range (IQR) 1.1–3.0 years]. Figures 1 and 2 show median serum phosphate and eGFR values over time for these TDF-exposed children, for the 12 months before and 24 months after starting TDF, grouped by age. Results suggest no clear decrease in serum phosphate or eGFR following the start of TDF, and although IQRs were large, indicating considerable variability between children, lower quartile values were considerably higher than the upper limits for moderate or greater serum phosphate gradings (0.96 mmol/l for age 2–14 years and 0.80 mmol/l for age ≥15 years) and mild reductions in eGFR (89 ml).
Twenty (4.4%) of the 456 children experienced a serum phosphate DAIDS grade at least 2 during follow-up, at a median (IQR) age of 9.4 (6.9–12.4) years. Only one child (0.2%) had a confirmed eGFR less than 60 ml/min per 1.73 m2, at age 10.3 years, which followed a confirmed serum phosphate DAIDS grade 2; 48 children had an eGFR 60–89 ml at some point during follow-up. Due to the rarity of eGFR less than 60 ml/min per 1.73 m2 values, subsequent analyses focused only on serum phosphate results.
Ten of the 20 children with a DAIDS grade at least 2 serum phosphate were on a TDF-containing ART regimen at the time of this event, whereas the other 10 children had no previous TDF exposure. For the 10 on TDF, events occurred at a median (IQR, range) of 18 (17–20, 6–42) months after starting TDF (Fig. 3). None were receiving more than 120% of the recommended paediatric dose of TDF (8 mg/kg) at the time of the event (two were taking <80% of the recommended dose, four were on the maximum adult dose of 300 mg/day and three were taking 150 mg/day). Figure 4 shows individual plots of serum phosphate results for these 10 children for periods both before and after the event. Eight of the 10 children stopped TDF at the time of the event, whereas two children remained on TDF after the event (cases 2, 6) albeit with limited follow-up. There was wide variation in the frequency and timing in which serum phosphate was measured, and results prior to TDF use were available for only five (50%) children (cases 3, 4, 8, 9, and 10). Most children had some evidence of a decline in serum phosphate following TDF initiation, and a rise following the event and TDF withdrawal (cases 1, 3, 4, 7, 8, 9, and 10), but in two, the decline prior to TDF withdrawal was steep (2, 5). Following the event, serum phosphate results normalized in six children (cases 1, 2, 3, 5, 7, and 10), but for four children (cases 4, 6, 8, and 9) there were too few measures (≤3) to confirm whether results normalized.
In a previous analysis we identified six children who had a reported renal adverse event while taking TDF , of whom four attended one of the seven hospitals included in this analysis. Three of these four had a DAIDS grade at least 2 within 3.5 months prior to the reported event [two cases of proximal renal tubular dysfunction (PRTD) and one renal toxicity], and stopped TDF within 3 weeks of the reported event. The other child's reported renal event was nephrocalcinosis (in combination with neutropenia and haematuria) which may well have been unrelated and would not necessarily affect serum phosphate levels. However, this child did experience a subsequent confirmed serum phosphate grade at least 2 two years following the reported renal event, but remained on TDF at last follow-up 1.5 years later.
For the case–control analysis the 20 children with a serum phosphate DAIDS grade at least 2 were matched to 60 controls, and characteristics of both groups are shown in Table 1. For most characteristics, including age, sex, CDC C events at ART initiation, and duration of ART, cases and controls were very similar, for example around 55% were female and median duration of ART was 4 years. However, 50% of cases had taken TDF in the previous 6 months, compared to only 18% of controls. In univariable analyses, only TDF exposure in the previous 6 months was associated with a confirmed DAIDS grade at least 2 [odds ratio (OR) = 4.81, 95% confidence interval (CI) 1.45–15.97]. In multivariable analyses, once the model had been adjusted for TDF exposure in the previous 6 months, no additional variables were associated with DAIDS grade at least 2.
Overall, the crude incidence rate of DAIDS grade at least 2 was 4.3 per 100 child-years (95% CI 2.2–8.4) in children taking a TDF-containing ART regimen compared to 0.9 per 100 child-years (95% CI 0.4–1.6) in those who had never taken TDF. In the Poisson model, again, only TDF exposure in the previous 6 months was associated with DAIDS grade at least 2 (rate ratio = 6.02, 95% CI 2.5–14.7, P < 0.001) (model results available on request).
Finally, the number of children meeting the case definition, serum phosphate DAIDS grade at least 2, was compared with the number with a serum phosphate less than LLN for that hospital. All those with DAIDS grade at least 3 also had values less than LLN. However, for the 13 children with DAIDS grade 2, 10 also had values greater than LLN, of whom seven were taking TDF. In the case–control model, there was some evidence that TDF use in the previous 6 months was again associated with serum phosphate less than LLN, but results do not reach statistical significance (OR = 3.00, 95% CI 0.78–11.51, P = 0.1), and no other measured variables were associated with this outcome.
Our study is the largest to date to investigate the association between use of TDF and risk of renal abnormality in HIV-1-infected children on ART. Of 456 children on ART included in our study, the overall prevalence of hypophosphataemia (DAIDS grade ≥2) was 4% over a median of 9 years follow-up, and only one child had an eGFR less than 60 ml/min per 1.73 m2, which itself followed a hypophosphataemic event. TDF use in the previous 6 months was the only factor associated with hypophosphataemia in both case–control and Poisson analyses, with those on TDF having five times the odds of DAIDS grade at least 2 (OR = 4.81, 95% CI 1.45–15.97), and six times the rate of DAIDS grade at least 2 (rate ratio = 6.02, 95% CI 2.5–14.7), compared to those without TDF exposure in the previous 6 months.
Although serum phosphate and eGFR levels appeared to be relatively stable in most children after starting TDF, renal events happened later, at a median (IQR) 18 months (17–20) after TDF start. For most children experiencing a DAIDS grade at least 2 whilst taking TDF, serum phosphate increased following TDF withdrawal, and returned to normal for six children, although for the other four there was insufficient follow-up time to assess this properly.
Our analysis has several important limitations. Firstly, as with other studies, we relied on serum phosphate and eGFR as indicators of renal impairment. However, they are not very sensitive; urinary phosphate measurements or other more sensitive indicators of tubular dysfunction such as β-2 microglobulinuria were not measured routinely in participating clinics, and so milder abnormalities in renal tubular function may have been missed. Secondly, there are recognized limitations of the Schwartz formula in estimating GFR, and potential differences in creatinine calibration between laboratories . Thirdly, we used DAIDS grades at least 2 as our definition of hypophosphataemia, despite some of these levels falling within the normal ranges for the laboratories in the participating hospitals. However, DAIDS grades were preferred as a standardized measure rather than using hospital normal ranges, which differed by hospital, age and sex and were not calibrated for comparison to each other. Despite this, phosphate levels below laboratory normal ranges were also associated with prior TDF use, although this was not statistically significant due to the small numbers. Fourthly, we found some discordance in the comparison of gradings and hospitals' normal ranges, with 10 children with a DAIDS grade 2 hypophosphataemia also falling within the hospital's normal range. Fifthly, we only identified 20 children who had experienced a serum phosphate DAIDS grade at least 2, and the CIs around our effect estimates are wide; further, we would have likely underestimated the potential effect of TDF on renal impairment had TDF been stopped in some children as soon as serum phosphate or eGFR was seen to be falling, but not yet reaching the outcome levels used in this analysis (confirmed DAIDS grade ≥2 or eGFR <60 ml/min per 1.73 m2). Finally, other studies have highlighted an association between TDF and lower bone mineral density [22,30,31], but we were unable to investigate this important aspect as participating clinics did not routinely measure bone mineral density in HIV-1-infected children on or not on TDF.
Nevertheless, our findings indicate that the risk of hypophosphataemia was significantly higher in children with TDF exposure in the previous 6 months, and results were consistent between two contrasting analytical approaches (case–control and Poisson). The crude incidence rate of DAIDS hypophosphataemia grade at least 2 was low but over four times higher in those taking a TDF-containing ART regimen compared to those who had never taken TDF. This incidence is similar to the incidence of abacavir hypersensitivity reaction in non-African adults and children .
Our previous study showed that TDF was more commonly prescribed to older, more ART-experienced children, and it might therefore be expected that this group has a higher risk of renal impairment. Although we attempted to control for these factors in our analysis, the higher risk associated with TDF use persisted after adjustment. Our study showed that once a renal event had occurred, TDF was appropriately stopped in the majority of children, and for most, serum phosphate measures subsequently returned to normal levels (although numbers were small). However, it is important to note that as TDF is presently often prescribed as part of salvage therapy, needing to discontinue its use has more significance in a context of limited options for subsequent ART regimens.
A phase II trial of tenofovir in children has recently finished and results are expected at the end of 2009. Our findings highlight the importance of providing longer-term renal outcome data for children taking TDF and also of comparing them with controls taking other ART drugs; it is notable that the DAIDS grade at least 2 events in our study occurred at a median of 18 months after TDF start, beyond the standard 48-week follow-up period for most RCTs. Our findings also highlight the importance of long-term biochemistry monitoring in children on ART, and in particular 3-monthly measurement of serum creatinine and phosphate levels while on TDF. We were not able to assess the usefulness of other measures, and in particular urinary markers of renal tubular damage, in our study, although a recent description of renal and bone toxicity in adults in London suggested that the urine protein/creatinine ratio proved to be a convenient test for renal disease . Consideration should also be given to measuring bone mineral density in children exposed to TDF and controls on other ART regimens, including at baseline to take into account the concomitant effects of HIV on mineralization.
We are grateful to the staff members at the seven hospitals participating in this case–control study for providing us with biochemistry data. In particular we thank Colin Ball and Sally Hawkins at King's College Hospital NHS Foundation Trust, Toni Tan and Cynthia Murphy at North Manchester General Hospital, Amanda Walsh at Our Lady's Children's Hospital, and Vivienne van Someren at the Royal Free Hampstead NHS Trust.
A.J. received a travel grant from Gilead to present this work at a conference. A.R. has organized educational meetings using unrestricted grants from Gilead. There are no conflicts of interest for all other authors.
This project was supported by a grant from Gilead Sciences, Inc. The funder had no role in the design and analysis of the study, or interpretation of the study's results.
Author contributors: A.J., K.L.B., W.S., D.D., A.R. and D.M.G. designed the study. K.B., H.L., M.S. and D.S. contributed data. K.L.B. analysed the data, and A.J. wrote the first draft of the paper. All authors contributed to the interpretation of the data, commented on the draft, and approved the final version.
CHIPS Steering Committee members: K.L. Boyd, K. Butler, K. Doerholt, S. Donaghy, D.T. Dunn, D.M. Gibb, A. Judd, E.G.H. Lyall, J. Masters, E. Menson, B. Murphy, V. Novelli, C.S. Peckham, A. Riordan, M. Sharland, D. Shingadia, P.A. Tookey, and G. Tudor-Williams.
The authors thank the families and staff from the following hospitals who participated in CHIPS (in alphabetical order):
Republic of Ireland: Our Lady's Children's Hospital Crumlin, Dublin: K. Butler, A. Walsh. UK: Birmingham Heartlands Hospital, Birmingham: Y. Heath, J. Sills, and S. Welch; Blackpool Victoria Hospital, Blackpool: N. Laycock; Bristol Royal Hospital for Children, Bristol: A. Finn, A. Foot, and L. Hutchison; Calderdale Royal Hospital, Halifax: G. Sharpe; Central Middlesex Hospital, London: M. Le Provost, and A. Williams; Chase Farm Hospital, Middlesex: I. Pollock; Chelsea and Westminster Hospital, London: D. Hamadache, E. G. H. Lyall, and P. Seery; Coventry and Warwickshire, Coventry: P. Lewis, J. Daglish; Derbyshire Children's Hospital, Derby: N. Ruggins, J. McIntyre; Derriford Hospital, Plymouth: P. Ward; Ealing Hospital, Middlesex: V. Shah, K. Sloper; Eastbourne District General Hospital, Eastbourne: G. Gopalakrishnan; Glasgow Royal Hospital for Sick Children, Glasgow: C. Doherty, R. Hague; Great Ormond St Hospital for Children, London: M. Clapson, S. Fasolo, J. Flynn, D. M. Gibb, N. Klein, K. Moshal, V. Novelli, and D. Shingadia; Harrogate District Hospital, Harrogate: P. Tovey; Hillingdon Hospital, London: A. Kakoo; Hinchingbrooke Hospital, H. Dixon; Homerton University Hospital, London: D. Gurtin; James Cook University Hospital, Middlesbrough: A. Fall; John Radcliffe Hospital, Oxford: A. Pollard, S. Segal; King's College Hospital, London: C. Ball, S. Hawkins, and D. Nayagam; Leeds General Infirmary, Leeds: P. Chetcuti; Leicester Royal Infirmary, Leicester: M. Green, and J. Houghton; Luton and Dunstable Hospital, Luton: M. Connan, M. Eisenhut; Mayday University Hospital, Croydon: J. Baverstock, J. Handforth; Milton Keynes General Hospital, Milton Keynes: P. K. Roy; Newcastle General Hospital, Newcastle: J. Clarke, K. Doerholt, and C. Waruiru; Newham General Hospital, London: C. Donoghue, E. Cooper, S. Liebeschuetz, and S. Wong; Ninewells Hospital and Medical School, Dundee: T. Lornie; Norfolk and Norwich Hospital, Norwich: C. Kavanagh; North Manchester General Hospital, Manchester: C. Murphy, T. Tan; North Middlesex Hospital, London: J. Daniels, E. G. H. Lyall, and B. Sampson-Davis; Northampton General Hospital, Northampton: F. Thompson; Northwick Park Hospital, Middlesex; M. Le Provost, A. Williams; Nottingham City Hospital, Nottingham: D. Curnock, A. Smyth, and M. Yanney; Queen Elizabeth Hospital, Woolwich: W. Faulknall, S. Mitchell; Raigmore Hospital, Inverness: T. Reddy; Royal Belfast Hospital for Sick Children, Belfast: S. Christie; Royal Berkshire Hospital, Reading: A. Gordon; Royal Children's Hospital, Aberdeen: D. Rogahn; Royal Cornwall Hospital, Truro: S. Harris; Royal Devon and Exeter, Exeter: A. Collinson, C. Hayes; Royal Edinburgh Hospital for Sick Children, Edinburgh: J. Mok; Royal Free Hospital, London: S. McKenna, V. Van Someren; Royal Liverpool Children's Hospital, Liverpool: C. Benson, A. Riordan; Royal London Hospital, London: B. Ramaboea, A. Riddell; Royal Preston Hospital, Preston: A. N. Campbell; Salisbury District General Hospital, Salisbury: N. Brown; Sheffield Children's Hospital, Sheffield: J. Hobbs, F. Shackley; Southampton General Hospital, Southampton: S. N. Faust; St George's Hospital, London: R. Chakraborty, S. Donaghy, R. Fluke, M. Sharland, S. Storey, and C. Wells; St Luke's Hospital, Bradford: S. Gorman; St Mary's Hospital, London: D. Hamadache, C. Hanley, E. G. H. Lyall, G. Tudor-Williams, C. Walsh, and S. Walters; St Thomas' Hospital, London: R. Cross, G. Du Mont, and E. Menson; Torbay District General Hospital, Torquay: J. Broomhall; University Hospital Lewisham, London: D. Scott, J. Stroobant; University Hospital of North Staffordshire, Stoke-on-Trent: P. McMaster; University Hospital of Wales, Cardiff: B. O'. Hare; West Cumberland Hospital, North Cumbria: D. Lee; Wexham Park, Slough: R. Jones; Whipps Cross Hospital, London: K. Gardiner; Whittington Hospital, London: H. McKinnon; and Wythenshawe Hospital, Manchester: D. Denning.
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