1. Poster 914
Effect of Tenofovir Disoproxil Fumarate (TDF) on Risk of Renal Impairment in HIV-1-infected Children on ART: Nested Case-control Study
Ali Judd, Katherine Boyd, Wolfgang Stöhr, David Dunn, Karina Butler, Andrew Riordan, Di M Gibb on behalf of the Collaborative HIV Paediatric Study (CHIPS)
MRC Clinical Trials Unit, London, UK; Royal Liverpool Children’s NHS Trust, Liverpool, UK; Our Lady’s Children’s Hospital, Dublin, Ireland
Contact for further information:
Ali Judd
MRC Clinical Trials Unit
222 Euston Road
London NW1 2DA, UK
P: +44 (0) E:
ABSTRACT
INTRODUCTION
RESULTS
Background: TDF is prescribed off-label for children using the adult tablet formulation. It has been associated with impaired renal function but there are few data in children. We describe renal function and phosphate levels in children in UK/Ireland on TDF and other ART.
Methods: Descriptive data were from the Collaborative HIV Paediatric Study, a cohort of ~95% of HIV-1 infected children treated in the UK/Ireland. Suspected adverse drug reactions (ADRs) were identified from reports to CHIPS and from voluntary, UK-wide, “Yellow Card” ADR reporting. Biochemistry results from 2002 onwards were obtained for 456 ART-exposed children (2-18yrs) seen at 7 hospitals. For the case control analysis, cases had confirmed hypophosphataemia DAIDS grade≥2; 3 controls per case were matched by hospital of attendance and censored at the time of the case’s event.
Results: 159/1,252 children in CHIPS had ever taken TDF. They were older at last follow-up (median 14.5 v 10.6yrs, p<0.001) and more had AIDS when starting ART (35 v 23%, p<0.001) than the rest of the cohort. 18% had >120% and 37% <80% of the recommended paediatric TDF dose (8mg/kg). 6 had a suspected renal ADR (PRTD/renal toxicity (5), renal failure (1)); 5/6 took concurrent ddI+LPV/r and subsequently stopped TDF. Biochemistry data indicated that 20 children had hypophosphataemia using DAIDS grading (including 4/6 with suspected TDF renal ADRs) of whom results for 8 fell within the hospital normal range, and 1 had an estimated glomerular filtration rate ≤60ml/min/1.73m2 (Schwartz formula). 50% (10/20) of cases v 18% (11/60) of controls had prior TDF exposure (p=0.005); hypophosphataemia in the 10 cases on TDF occurred at median 18 months (IQR 17-20) post-TDF start. TDF exposure in the previous 6 months was associated with hypophosphataemia (OR=4.8, 95%CI ), but recent use of other ART, baseline CD4/HIV-1 RNA, CDC stage, and sociodemographics were not.
Conclusions: Although unlicensed in children, TDF is prescribed in this cohort, although considerable under/overdosing occurs. 6 children had suspected renal ADRs while on TDF, most while also taking ddI+LPV/r. Overall, serum phosphate and eGFR levels were stable 12 months after starting TDF but renal events happened later. Recent TDF exposure was associated with higher odds of hypophosphatemia, suggestive of tubular leak, however numbers were small and 40% values were within the hospital normal range. Longer term renal outcome data are needed, as well as data on bone mineral density.
TDF and renal disease
Some ART drugs have been linked to renal disease, including TDF
Anecdotal case reports in adults and children describe TDF-related severe tubular dysfunction, which is generally reversible after TDF has been withdrawn
RCTs comparing TDF-containing v. other ART regimens in adults with normal baseline renal function have generally reported similar renal safety profiles
Adult cohort studies have found only infrequent hypophosphataemia and slight or modest decreases in creatinine clearance, in those on TDF-containing regimens, and no increased risk of discontinuation of therapy or adverse events.
TDF in children
TDF is not licensed for use in HIV-infected children <18 years of age
TDF is often used off-label in this population as part of salvage therapy
Two small studies which followed ART-experienced children on TDF-containing regimens found no evidence of impaired glomerular or tubular renal function
Characteristics of children taking TDF
13% (159/1252 in CHIPS) took TDF as part of combination ART, and were:
older (median 14.5 v years at last follow-up, p<0.001)
more likely to have presented before 1996 (43% v 17%, p<0.001)
more likely to have progressed to AIDS before combination ART (35% v 23%, p<0.001)
The median age at first prescription of TDF was 11.8 years ( )
Reasons for starting TDF included: immunologic/clinical failure of the previous regimen (47%); results of resistance testing (26%); regimen simplification or replacement (16%).
Previous and concurrent antiretroviral regimens
TDF was part of 1st line HAART for 22%, 2nd line for 61%, and 3rd line for 17%
38% of those on TDF had previous triple class exposure
TDF regimens contained at least one other NRTI (89%), PI (72%) and/ or NNRTI (32%)
NRTIs were ddI (37%, mainly in earlier years), 3TC (18%), ABC (17%), AZT (11%)
PIs were mainly LPV/r (59%)
Dosing
73% took the maximum once-daily adult dose of 300mg and 20% took half the adult daily dose
The rest took a variety of doses which were made by dissolving the tablet and giving a proportion of the total mixture
Figure 1 shows all doses at the start of a new regimen and also at the time of absolute dose changes by weight across different ages
Dose declines by weight as age increases, with a slight jump from lower to higher dose by weight at ~10 years of age when children increase from a half to full tablet per day
For those not on the maximum once-daily 300mg dose, 23 (18%) were first dosed at >120% of the suggested dose (8mg/kg/day), and 14 (37%) at <80% of the suggested dose
Adverse drug reactions (ADRs) and stopping TDF
12/159 (8%) children were reported to have ADRs whilst on TDF (for a median 570 days) and subsequently stopped TDF
10/12 also took ddI and 11 also took LPV/r
3/12 received ≥120% of the suggested dose of TDF
Six possible renal events were associated with concurrent TDF use (co-administered with ddI and LPV/r in 5 of the 6 cases), giving an overall rate of renal ADRs in those on TDF of 2.2/100 child years.
Serum phosphate and eGFR pre- and post-TDF
Figure 2a/b suggests no overall decrease in phosphate/eGFR after TDF start
4% (20/456) of children on combination ART at 7 main hospitals in CHIPS had a serum phosphate DAIDS grade ≥2, and 0.2% (1/456) an eGFR grade≥3
10/20 with DAIDS ≥2 were on TDF at the time of the event
Figure 3 shows individual plots of phosphate results for these 10, indicating wide variation in the frequency and timing of measures
8 of the 10 stopped TDF at the time of the event; 2 stayed on TDF (#2 and #6) but follow-up after the event was short
40% of serum phosphate measures meeting the DAIDS ≥2 criterion were within the respective hospital’s normal range
Predictors of hypophosphataemia
Most characteristics of cases and controls were similar (eg ~55% were female, and median duration of ART was ~4 years, in each group)
50% of cases had taken TDF in the previous 6 months, v. 18% of controls
In the matched case-control and Poisson analyses, only TDF exposure in the previous 6 months was associated with serum phosphate DAIDS ≥2 (case control OR=4.81, 95%CI ; Poisson RR=6.47, 95%CI )
Figure 3: Individual plots of serum phosphate results for children with phosphate grade ≥2 while taking TDF
Solid vertical line indicates point at which TDF was started. Dashed vertical line indicates point of last follow-up in CHIPS
AIM
Describe children taking TDF, dosing and adverse drug reactions (ADRs)
Measure the effect of TDF on risk of renal impairment in children
METHODS
CONCLUSIONS
NSHPC and CHIPS
HIV-infected children in the UK/Ireland are notified to the National Study of HIV in Pregnancy & Childhood, and followed up in CHIPS (Collaborative HIV Paediatric Study)
Descriptive analyses
Doses were calculated using the most recent weight measure before dosing; those on the maximum adult daily dose were excluded from under/overdosing calculations
ADRs in CHIPS were matched to suspected adverse drug reactions reported to the Medicines and Healthcare products Regulatory Agency’s (MHRA) Yellow Card Scheme, which is the UK's voluntary, spontaneous SAE reporting scheme.
Nested case-control & Poisson analyses
Biochemistry results from (when TDF was licensed in adults) were obtained for 456 ART-exposed children aged 2-17 years who were patients receiving direct (rather than shared) care at the seven hospitals in CHIPS prescribing TDF most frequently
Serum phosphate was graded using the Division of AIDS (DAIDS) AE tables1; estimated Glomerular Filtration Rate (eGFR) was calculated from serum creatinine levels using the Schwartz formula, and graded using National Kidney Foundation guidelines2
The case definition was confirmed3 phosphate grade ≥2 or eGFR stage ≥3
3 randomly selected controls were matched to their respective cases by hospital. Conditional logistic regression identified risk factors for being a case (p<0.05)
A Poisson model investigated the effect of current and cumulative exposure to TDF on risk of being a case, by dividing each patient’s follow-up into consecutive 3 month periods and allowing for time-updated variables (age, year, CDC stage, last CD4% & HIV-1 RNA), hospital, sex and ethnicity. Patients were censored at the outcome date, the last available biochemistry result, or the end of CHIPS follow-up, whichever was first.
Statistical analysis was performed using STATA 10.0 (StataCorp LP, Texas, USA).
Figure 2: Median serum phosphate and eGFR before/after TDF start
(a) serum phosphate (b) eGFR
In the UK/Ireland, TDF was prescribed to older, more ART-experienced children who presented in earlier years
TDF was most commonly prescribed with ddI and/or LPV/r, and was associated with considerable under- and over-dosing
12 (8%) children on TDF had subsequent ADRs, a median 570 days after starting TDF, of whom 10 also took ddI and 11 LPV/r
6 were renal events
The overall incidence of hypophosphataemia was low, but was associated with TDF exposure in the last 6 months
40% of serum phosphate levels classified as hypophosphataemia (DAIDS grade≥2) were within the normal range for the hospital’s laboratory
Longer-term renal outcome data are needed for patients both taking TDF and taking other regimens
Other studies have highlighted an association between TDF and lower bone mineral density, which was not investigated in our study
Figure 1: TDF dosing by age
Note: Data are censored at the TDF stop date. Values are only plotted where n≥7
Notes for Methods section:
1: Grade 1, “mild” (age: 2-14 years, mmol/L; ≥15 years: 0.81-<LLN); grade 2, “moderate” (2-14, mmol/L; ≥15, mmol/L); grade 3, “severe” (2-14, mmol/L; ≥15, mmol/L); grade 4, “potentially life threatening” (2-14, <0.48 mmol/L; ≥15, <0.32 mmol/L).
2: Stage 1, “normal or increased GFR” (>=90mL/min/1.73m2); stage 2, “mild reduction of GFR“ (60-89mL); stage 3, “moderate reduction of GFR” (30-59mL); stage 4, “severe reduction of GFR” (15-29mL); stage 5, “kidney failure” (<15mL)
3: 2 results within 6 months
ACKNOWLEDGEMENTS
We thank staff and families from the hospitals collaborating in CHIPS/ NSHPC. CHIPS is funded by the UK Department of Health. Additional support has been obtained from Bristol-Myers Squibb, Boehringer-Ingelheim, GlaxoSmithKline, Roche, Abbott and Gilead Sciences.