Viral load blips in HIV infected children from the CHIPS cohort: what do they mean?

1. Background At blip Difference to Difference to Table 2: Summary of CD4 and CD8 before, during and after a blip previous post 3 CD4 (cells/mm ) 858 (634 - 1314) - 20 ( - 127 - +140) +17 ( - 117 - +130) p=0.85 p=0.44 3 CD8 (cells/mm ) 970 (720 - 1190) +4 ( - 178 - +128) +35 ( - 110 - +190) p=0.78 p=0.07 • Blips significantly more commo n with: • initiating HAART younger • 1 year of suppression • second-line • non-NNRTI containing HAART Methods Univariate models Multivariate model Sex (girls vs boys) p=0.05 Age at HAART (per year older) CD4% at HAART (per 5% increase) Viral load at HAART (per log10 copies/ml) B/C event before HAART Current Age 0-3 years 4-12 years 13 + years 1997-9 Current calendar year 2000-2 2003-5 <1 year p=0.03 Duration of suppression 1-2 years Summary 2-3 years 3-4 years 4+ years First-line p<0.001 Results Second-line Previous blips None p=0.22 1 or more p=0.03 NNRTI-containing ART PI-containing ART 0 1 2 3 4 0 1 2 3 4 Incidence Rate Ratio (IRR and 95% CI) References Acknowledgments • Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 Viraemia (Blips) and Drug Resistance in Patients Receiving HAART. JAMA 2005;297(7):817-29. • Havlir DV, Bassett R, Levitan D, et al. Prevalence and Predictive Value of Intermittant Viraemia With Combined HIV Therapy. JAMA 2001;286(2):171-9. • Mira JA, Macias J, Nogales C, et al. Transient Rebounds of Low-Level Viraemia Among HIV-Infected Patients Under HAART Are Not Associated With Virological or Immunological Failure. Antiretroviral therapy 2002;7(4):251-6. • Sklar PA, Ward DJ, Baker RK, et al. Prevalence and Clinical Correlates of HIV Viremia ('Blips') in Patients With Previous Supression Below the Limits of Quantification. AIDS 2002;16(15):2035-41. • Gibb DM, Duong T, Tookey PA, Sharland M, Tudor-Williams G, Novelli V, et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland. British Medical Journal 2003;327(7422):1019. • Ades AE, Davison CF, Holland FJ, Gibb DM, Hudson CM, Nicholl A, et al. Vertically transmitted HIV infection in the British Isles. BMJ 1993; 306:1296-1299. 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 • 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) • 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: • 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. • Objectives • 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. • 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]. • 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]. Figure 2: Univariable and multivariable predictors of blips: Poisson Regression Population:Children who start HAART (3 or more drugs from 2 or more classes or including TDF/ABC) without prior exposure to ART. Switching to second line: HIV-1 RNA >50 copies/ml, and any switch of 3 or more drugs (regardless of reported reason) or a switch of 2 drugs with reported reasons being for ‘failure’ (CD4/viral load/clinical failure or resistance). 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). 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. 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. • 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. 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). Table 1: Characteristics of blips and children who blip • 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. Funding: NSHPC is funded by the Health Protection Agency, and has also received support from the UK Department of Health and the Medical 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; BlackpoolVictoria 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, KSloper; GlasgowRoyal 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. Figure 1: Proportion of children reaching suppression who blip by age at HAART initiation 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: kjl@ctu.mrc.ac.uk