Transcript Document

Viral load blips in HIV infected children
from the CHIPS cohort: what do they mean?
Delane Shingadia1, Katherine J Lee2, Deenan Pillay3, A Sarah Walker2, Gareth Tudor-Williams4, Ali Judd1 and Diana M Gibb1 on behalf of
the Collaborative HIV Paediatric Study (CHIPS) Steering Committee.
1
Great Ormond Street Hospital for Sick Children, London, UK; 2 MRC Clinical Trials Unit, London, UK; 3 University College London, London, UK; 4 St Mary’s Hospital, London,
UK
Background
During periods of viral suppression on antiretroviral therapy (ART) many HIV-infected
individuals have transient periods of viraemia, where HIV RNA viral load temporarily becomes
detectable:
• these “blips” in viral load are thought to represent random biological and statistical variation
rather than clinically significant elevations in viraemia [1]
• not a predictor for longer-term virological or immunological failure in adults [2-4].
Although there are a number of papers describing blips in adults on ART, there are no
reports of blipping in children. As children generally have lower virological suppression
rates than adults, and higher viral load at ART initiation, patterns of blipping may be different
in children.
• Blips occurred in children of all ages from 1 to 15, although were more common in
children who initiated HAART at younger ages (Figure 1). Age at HAART initiation was a
better predictor of blipping than current age (Figure 2).
• Blips occurred after a median of 1.4 years sustained virological suppression.
• The average blip viral load was 118 copies/ml during first-line and 167 during second-line
(ranksum p=0.68), with 23 (21%) and 17 (16%) being >500 and >1000 copies/ml
respectively and all under 40,000 copies/ml.
• Blips have little effect on CD4 or CD8 (Table 2)
Figure 2: Univariable and multivariable predictors of blips: Poisson Regression
Univariate models
Multivariate model
Sex (girls vs boys)
Age at HAART (per year older)
Objectives
p=0.05
CD4% at HAART (per 5% increase)
Viral load at HAART
(per log10 copies/ml)
To explore the incidence, characteristics, predictors and subsequent consequences of blips in
children with virologic suppression (<50 copies/ml) in the Collaborative HIV Paediatric Study
(CHIPS) cohort of HIV infected children in the UK and Ireland.
Blips significantly more commo n with:
• initiating HAART younger
• 1 year of suppression
• second-line
• non-NNRTI containing HAART
B/C event before HAART
0-3 years
4-12 years
13 + years
Current Age
The Collaborative HIV Paediatric Study (CHIPS)
CHIPS is a multicentre cohort of HIV-infected children under care in the UK and Ireland since
1996 [5]. Children are under care at one of 39 hospitals in the UK and Ireland, and account for
approximately 90% of all children reported to the National Study of HIV in Pregnancy and
Childhood (NSHPC) and alive in 2005 [6].
1997-9
2000-2
2003-5
Current calendar year
Duration of
suppression
<1 year
1-2 years
2-3 years
3-4 years
4+ years
p=0.03
First-line
Second-line
Methods
Population: Children who start HAART (3 or more drugs from 2 or more classes or
Previous blips
including TDF/ABC) without prior exposure to ART.
p<0.001
None
1 or more
p=0.22
NNRTI-containing ART
Switching to second line: HIV-1 RNA >50 copies/ml, and any switch of 3 or more
p=0.03
PI-containing ART
drugs (regardless of reported reason) or a switch of 2 drugs with reported reasons
being for ‘failure’ (CD4/viral load/clinical failure or resistance).
0
Period of sustained virological suppression: the time from the first of two
consecutive undetectable viral loads (<50 copies/ml) to the last viral load <50 copies/ml
before confirmed viral load failure (persistent viral load >50 copies/ml) or switch to
second- or third-line treatment.
Blip: one or more detectable viral loads 50 copies/ml between two undetectable viral loads
(<50 copies/ml) <280 days apart, during a period of virological suppression, without a
change in treatment (ignoring single drug substitutions for simplification/personal
reasons and single drug intensifications).
STATISTICAL METHODS
We described the blips in terms of their viral load and changes in CD4 and CD8, and
evaluated predictors of the blipping rate during periods of sustained virological suppression
using univariable and multivariable Poisson regression based on backwards elimination
using the Akaike Information Criteria (AIC). Finally we explore the effect of blipping on
virological failure using time-dependent models.
Results
595 of the 1065 children enrolled in CHIPS to December 2005 started HAART naïve of
whom 347 (58%) ever achieved sustained virological suppression <50 copies/ml on either
first or second-line. 78 of these children experienced a blip (Table 1).
Second-line
595 (100%)
300 (50%)
132 (100%)
60 (45%)
684.6
98.8
59
(20%)
19
(14%)
(4%)
(1%)
(1%)
81
11 (8, 14)
12
5
2
0
43
12
2
2
22
95.2
19 (13, 29)
118 (51, 39839)
7.2 (4.7, 11.0)
(32%)
(20%)
(8%)
(3%)
(0%)
28
25 (17, 39)
9
17.6
15 (5, 43)
167 (51, 36442)
8.7 (6.0, 12.3)
Figure 1: Proportion of children reaching suppression
who blip by age at HAART initiation
% of children reaching suppression who blip
10
20
30
40
50
2
3
4 0
1
2
3
Incidence Rate Ratio (IRR and 95% CI)
4
Table 2: Summary of CD4 and CD8 before, during and after a blip
At blip
3
858 (634 -1314)
3
970 (720 -1190)
CD4 (cells/mm )
CD8 (cells/mm )
Difference to
previous
-20 (-127-+140)
p=0.85
+4 (-178-+128)
p=0.78
Difference to
post
+17 (-117-+130)
p=0.44
+35 (-110-+190)
p=0.07
Using time dependent models for the outcome virological failure:
• no evidence for a higher rate of virological failure in children who had ever blipped
(HR=0.74 [95% CI 0.46-1.17] for having blipped compared to never having blipped,
p=0.20: adjusted for pre-HAART variables – sex, age, CD4, viral load and CDC B/C
events; line of ART; and current calendar year)
• children who blipped in the last year (adjusted HR=0.93 [0.59-1.47], p=0.77), or
blipped to >1000 copies/ml (adjusted HR=0.84 [0.35-2.06], p=0.71) were also not at
higher risk of subsequent virological failure.
Summary
Table 1: Characteristics of blips and children who blip
First-line
Number of children
Children reaching sustained virological
suppression
Child years at risk with sustained
suppression
Children blipping (% of those reaching
sustained suppression) (see Figure 1)
1 blip
2 blips
3 blips
4 blips
Total number of blips
Blip rate (per 100 child years) (95% CI)
After first blip
Number of subsequent blips
Child years at risk after first blip
Rate (per 100 child years) (95% CI)
Viral load at blip (Geometric mean (range))
Age at blip (years) (median (IQR))
1
Note: duration of suppression categorised into years as in the univariate model was not a
significant predictor in the multivariable model, but children suppressed for more than 1
year had significantly higher blipping rates than those suppressed for <1 year.
First-line
Second-line
• Transient rises in viral load are fairly common, arising in 22% of children with maximal
suppression on HAART.
• Blipping is more common: in children starting HAART at younger ages
in children on second-line therapy
after a previous blip
in children on non-NNRTI containing regimens
in children suppressed for more than one year
• The fact that we were able to identify a number of statistically significant predictors of
blipping suggests there may be causes beyond natural or assay variation in children.
• This is in contrast to at least one study in adults which found no significant predictors of
blipping [4], potentially due to adherence which can be more challenging in children who
depend on a caregiver for medication and are often unaware of their diagnosis.
• But blips have little effect on CD4 and CD8, and do not increase subsequent rate of
virological failure.
Acknowledgments
Funding:
NSHPC is funded by the Health Protection Agency, and has also received support from the UK Department of Health and the Medic al Research Council.
CHIPS is funded by the Department of Health and in the past received additional support from Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche, Abbott, and
Gilead.
Committees and participants (in alphabetical order):
CHIPS Steering Committee: K Butler, K Doerholt, S Donaghy, DT Dunn, T Duong, DM Gibb, A Judd, EGH Lyall, J Masters, E Menson, V Novelli, C Peckham, A Riordan, M
Sharland, D Shingadia, PA Tookey, G Tudor-Williams, G Wait
MRC Clinical Trials Unit: DT Dunn, T Duong, L Farrelly, DM Gibb, D Johnson, A Judd, G Wait, AS Walker
National Study of HIV in Pregnancy & Childhood, Institute of Child Health: J Masters, C Peckham, PA Tookey
We thank the staff, families & children from the following hospitals who participate 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; Blackpool Victoria Hospital, Blackpool: N Laycock; Bristol Royal Hospital for Children, Bristol: A Finn, A
Foot, L Hutchison; Central Middlesex Hospital, London: M Le Provost, A Williams; Chase Farm Hospital, Middlesex; Chelsea and Westminster Hospital, London: D Hamadache,
EGH Lyall, P Seery; Ealing Hospital, Middlesex: V Shah, K Sloper; Glasgow Royal Hospital for Sick Children, Glasgow: C Doherty, R Hague; Great Ormond St Hospital for
Children, London: M Clapson, S Fasolo, J Flynn, DM Gibb, N Klein, K Moshal, V Novelli, D Shingadia; Hillingdon Hospital, London; Homerton University Hospital, London: D
Gurtin; John Radcliffe Hospital, Oxford: A Pollard, S Segal; King's College Hospital, London: C Ball, S Hawkins, D Nayagam; Leeds General Infirmary, Leeds: P Chetcuti;
Leicester Royal Infirmary, Leicester: M Green, 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: PK Roy; Newcastle General Hospital, Newcastle: J Clarke, K Doerholt, C Waruiru; Newham General Hospital,
London: C Donoghue, E Cooper, S Liebeschuetz, S Wong; Ninewells Hospital and Medical School, Dundee: T Lornie; North Manchester General Hospital, Manchester: C
Murphy, T Tan; North Middlesex Hospital, London: J Daniels, EGH Lyall, 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, M Yanney; Queen Elizabeth Hospital, Woolwich: W Faulknall, S
Mitchell; Royal Belfast Hospital for Sick Children, Belfast: S Christie; 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: AN Campbell; Sheffield Children's Hospital, Sheffield: J Hobbs, F Shackley; St George's Hospital, London: R Chakraborty, S Donaghy, R Fluke, M Sharland, S
Storey, C Wells; St Mary's Hospital, London: D Hamadache, C Hanley, EGH Lyall, G Tudor-Williams, C Walsh, S Walters; St Thomas' Hospital, London: R Cross, G Du Mont, E
Menson; 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; Wexham Park, Slough: R Jones; Whipps Cross Hospital, London: K Gardiner; Whittington Hospital, London.
References
1.
0
<1
1-3
4-8
Age at HAART initiation
Number of children
51 7
66 16
110 21
5-12
13+
2.
54 12
19
4
3.
Contact: Dr Katherine J Lee,
Medical Research Council Clinical Trials Unit, 222 Euston Road, London, NW1 2DA.
Tel +44 (0) 20 7670 4700. Fax +44 (0) 20 7 670 4818.
Email: [email protected]
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