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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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
case–control study; Ireland; paediatrics; renal abnormality; tenofovir disoproxil fumarate; UK