Long-term virological outcome in HIV-infected children on ART in the UK/ Ireland

Trinh Duong, Intira Jeannie Collins, Ali Judd, Katja Doerholt, Caroline Foster, Delane Shingadia, Karina Butler, Esse Menson, David Dunn, Di Gibb

on behalf of the Collaborative HIV Paediatric Study (CHIPS)

• Two large randomized clinical trials showed conflicting results regarding response to first-line regimen:

PENPACT 1 (median age 6.5 years)No difference in reduction in viral load at 4 years between PI versus NNRTI-based initial regimens.

P1060 (age <3 years): Rate of treatment failure (virologic failure, treatment discontinuation or death) by 24 weeks was higher in the NVP compared to LPV/r arm.

• In observational cohort studies :

EPPICC infants study, 4-drug NNRTI-based regimens had superior virological and immunological response at 12 months.

Cohorts in South Africa and Botswana showed longer time to virological failure among children on efavirenz- versus nevirapine-based initial ART treatment (Davies et al. JAIDS 2011, Lowenthal et al. JAMA 2012).

• Data on long term outcomes by first line regimens are needed.

Background

Objectives

To assess factors at ART initiation associated with

• viral load suppression (<400 c/mL) within 12 months

• virological failure (VF) during follow-up

Date of VF defined as the earliest of: confirmed rebound >400 c/ml (2 consecutive measurements >400 c/ml

within 6 months) after previous suppression

unconfirmed rebound followed by treatment modification (changing ≥2 drugs) or death within 6 months

- viral load>400 c/ml after 12 months without previous suppression

Methods

• Included children aged <18 years who were ART naïve and initiated on ≥3 ART drugs (excluding unboosted PI-based and triple NRTI regimens) enrolled in the UK/Ireland Collaborative HIV Paediatric Study (CHIPS).

• Analysed time from ART initiation to

• Poisson mixed models assessed factors associated each virological outcome, allowing for clinic effects.

• Analyses were based on “intention-to-continue treatment”, ignoring treatment changes and interruptions. Missing data for covariates were imputed.

- initial suppression <400 c/ml within 12 months

- virological failure during study follow-up

NVP+2NRTI(n=260)

EFV+2NRTI(n=404)

Boosted PI+NRTI 1

(n=197)

NNRTI+3NRTI 2

(n=118)

Male (%) 125 (48%) 189 (47%) 84 (43%) 58 (49%)

Age (years), median (IQR)

4.0 (1.5-8.6)

10.3 (6.8-12.9)

9.0 (3.2-12.9)

0.6(0.3-2.4)

CD4%, median (IQR) 17 (11-23)

13 (8-18)

16 (11-21)

16 (8-28)

Viral load, median (IQR) log10(c/ml)

5.0 (4.4-5.5)

4.8 (4.3-5.2)

4.9 (4.1-5.3)

5.7 (5.2-5.9)

Previous AIDS (%) 33 (13%) 55 (14%) 39 (20%) 58 (49%)

Baseline characteristics [n=979]

1. 176/197 (89%) in PI group on LPV/r, 13 (7%) atazanavir and 8 (4%) darunavir. 181 (92%) children on 2NRTIs and 16 (8%) 3NRTIs.

2. 13/118 (11%) in NNRTI+3NRTI group on EFV, all aged>3 years.

<2000 2000/03 2004/07 2008-0%

20%

40%

60%

80%

100%

<2000 2000/03 2004/07 2008-0%

20%

40%

60%

80%

100%

Distribution of first-line regimen by calendar period

Number of children 27 85 90 49

Number of children 35 174 273 246

Age <3 years [n=251] Age ≥3 years [n=728]

NVP+2NRTI EFV+2NRTI PI+NRTI NNRTI+3NRTI

Pro

port

ion

of c

hild

ren

(%)

Pro

port

ion

of c

hild

ren

(%)

NVP(n=260)

EFV(n=404)

PI(n=181)

Number of children (%)

ABC+3TC 74 (29) 250 (62) 109 (55)

ZDV+3TC 113 (44) 63 (16) 37 (19)

d4T+3TC 24 (9) 19 (5) 6 (3)

ddI+d4T 44 (17) 7 (2) 4 (2)

TDF+FTC 2 (1) 55 (14) 17 (9)

Other 3 (1) 10 (3) 8 (4)

• Nearly all of children on 4-drug regimens took ZDV+3TC+ABC: all of the 16 on PI regimens and 115/118 (98%) on NNRTI regimens.

NRTI backbone among 3-drug regimens

Proportion with virological suppression <400 c/ml by 12 months

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

up

pre

ssed

0 3 6 9 12

PI+NRTI

NVP+2NRTI

NNRTI+3NRTI

Months from starting ART

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n s

up

pre

ssed

0 3 6 9 12

EFV+2NRTI

Months from starting ART

Age ≥3 yearsAge <3 years

PI+NRTINVP+2NRTI

NNRTI+3NRTI

First-line regimen Overall Age < 3 years Age ≥ 3 years

NVP+2 NRTI

EFV+2NRTI

Boosted PI

NNRTI+3 NRTI

1

1.18 (0.97-1.44)

0.90 (0.71-1.13)

1.00 (0.76-1.32)

P=0.03

Association between type of first-line regimen and suppression by 12 months

Adjusted for baseline age, CD4, HIV-1 RNA viral load, and pretreatment AIDS diagnosis,. calendar period and clinic effects,

Adjusted rate ratio (95% CI)

First-line regimen Overall Age < 3 years Age ≥ 3 years

NVP+2 NRTI

EFV+2NRTI

Boosted PI

NNRTI+3 NRTI

1

1.18 (0.97-1.44)

0.90 (0.71-1.13)

1.00 (0.76-1.32)

1

-

0.85 (0.57-1.26)

1.04 (0.73-1.45)

1

1.15 (0.93-1.43)

0.91 (0.70-1.19)

0.94 (0.60-1.48)

P=0.03 P for test for interaction= 0.67

Association between type of first-line regimen and suppression by 12 months

Adjusted rate ratio (95% CI)

Adjusted for baseline age, CD4, HIV-1 RNA viral load, and pretreatment AIDS diagnosis,. calendar period and clinic effects

Other predictors of suppression by 12 months

Factors at ART initiationRate ratio (95% CI) P

Age (years) <1 1-4 5-9 ≥10

11.31 (1.02-1.68)1.60 (1.14-1.92)1.68 (1.23-2.07)

<0.001

Viral load per log10(copies/ml) 0.88 (0.82-0.95) 0.001

Year 1996-1999 2000-2003 2004-2007 2008-2012

11.21 (0.86-1.71)1.46 (1.04-2.05)1.68 (1.18-2.41)

0.003

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n

of

chil

dre

n

0 12 24 36 48 60

PI+NRTI

NVP+2NRTI

NNRTI+3NRTI

Months from starting ART

Age <3 years

0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n o

f ch

ild

ren

0 12 24 36 48 60

PI+NRTI

NVP+2NRTI

EFV+2NRTI

NNRTI+3NRTI

Months from starting ART

Age ≥3 years

Proportion with virological failure during study follow-up 1

1. Median overall follow-up from ART initiation = 5.53 (IQR 2.7-8.3) years

Association between type of first-line regimen and virological failure

First-line regimen Overall Age < 3 years Age ≥ 3 years

NVP+2 NRTI

EFV+2NRTI

Boosted PI+NRTI

NNRTI+3 NRTI

1

0.54 (0.40-0.73)

0.66 (0.46-0.93)

0.59 (0.39-0.90)

P<0.001

Adjusted rate ratio (95% CI)

Adjusted for baseline age, CD4, HIV-1 RNA viral load, and pretreatment AIDS diagnosis,. calendar period and clinic effects.

Association between type of first-line regimen and virological failure

First-line regimen Overall Age < 3 years Age ≥ 3 years

NVP+2 NRTI

EFV+2NRTI

Boosted PI+NRTI

NNRTI+3 NRTI

1

0.54 (0.40-0.73)

0.66 (0.46-0.93)

0.59 (0.39-0.90)

1

-

0.67 (0.35-1.28)

0.69 (0.42-1.13)

1

0.50 (0.36-0.68)

0.63 (0.42-0.95)

0.43 (0.19-0.96)

P<0.001 P for test for interaction= 0.60

Adjusted for clinic effects, age, calendar period, baseline CD4, HIV-1 RNA viral load, and pretreatment AIDS diagnosis.

Adjusted rate ratio (95% CI)

Association between type of first-line regimen and virological failure, further adjusted for NRTI-backbone

(including 3-drugs regimens only)

First-line regimen Overall Age < 3 years Age ≥ 3 years

NVP+2 NRTI

EFV+2NRTI

Boosted PI+NRTI

1

0.57 (0.41-0.78)

0.66 (0.45-0.96)

1

-

0.67 (0.33-1.37)

1

0.51 (0.37-0.71)

0.66 (0.44-1.00)

P=0.002 P for test for interaction= 0.87

Adjusted rate ratio (95% CI)

Adjusted for baseline age, CD4, HIV-1 RNA viral load, and pretreatment AIDS diagnosis,. calendar period, clinic effects and NRTI backbone

Other predictors of virological failure

Factors at ART initiationRate ratio (95% CI) P

Age (years) <1 1-4 5-9 ≥10

10.81 (0.56-1.17)1.02 (0.70-1.48)1.75 (1.18-2.60)

<0.001

Year 1996-1999 2000-2003 2004-2007 2008-2012

10.75 (0.51-1.09)0.46 (0.31-0.68)0.44 (0.28-0.71)

<0.001

0

0.05

0.10

0.15

0.20

0 12 24 36 48 60

NVP

EFV

Months from starting ART

Time to discontinuation of initial NNRTI due to toxicity/adverse event

Pro

port

ion

of c

hild

ren

• Among children in the UK/Ireland, 3-drug EFV-based and 4-drug NNRTI-based regimens appeared at least as effective as 3-drug PI-based regimens in maintaining virological suppression.

• NVP was associated with increased risk of virological failure compared to EFV.

• Findings may be affected by residual confounding from selection bias in regimen choice.

Summary

Possible reasons: - choice of NRTI backbone - NVP under-dosing - differences in rate of toxicity - NVP dose-escalation strategy

Study limitations:

• Study had insufficient power to:

Future work:

• Findings to be verified and investigated further in an EPPICC analysis including >3000 children from Europe and Thailand.

Compare regimen types stratified by NRTI backbone

Assess whether differences in efficacy between regimen may have diminished over calendar time

Estimate accurately the absolute differences in efficacy between regimens by age and calendar period.

AcknowledgementsThe Collaborative HIV Paediatric Study is funded by the NHS (London Specialised Commissioning Group) and has received additional support from Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Roche, Abbott, and Gilead Sciences

We thank the staff, families & children from all the hospitals who participate in CHIPS:Republic of Ireland: Our Lady's Children’s Hospital Crumlin, Dublin.UK: Birmingham Heartlands Hospital, Birmingham; Blackpool Victoria Hospital, Blackpool; Bristol Royal Hospital for Children, Bristol; Calderdale Royal Hospital, Halifax; Central Middlesex Hospital, London; Chase Farm Hospital, Middlesex; Chelsea and Westminster Hospital, London; Coventry & Warwickshire University Hospital, Coventry; Derbyshire Children’s Hospital, Derby; Derriford Hospital, Plymouth; Ealing Hospital, London; Eastbourne District General Hospital, Eastbourne; Glasgow Royal Hospital for Sick Children, Glasgow; Great Ormond St Hospital for Children, London; Halliwell Children’s Centre, Bolton; Harrogate District Hospital, Harrogate; Hillingdon Hospital, London; Hinchingbrooke Hospital, Huntingdon; Homerton University Hospital, London; Huddersfield Royal Infirmary, Huddersfield; Ipswich Hospital, Ipswich; James Cook Hospital, Middlesbrough; James Paget Hospital, Great Yarmouth; John Radcliffe Hospital, Oxford; King's College Hospital, London; Leeds General Infirmary, Leeds; Leicester Royal Infirmary, Leicester; Luton and Dunstable Hospital, Luton; Mayday University Hospital, Croydon; Milton Keynes General Hospital, Milton Keynes; Newcastle General Hospital, Newcastle; Newham General Hospital, London; Ninewells Hospital and Medical School, Dundee; Norfolk & Norwich Hospital, Norwich; North Manchester General Hospital, Manchester; North Middlesex Hospital, London; Northampton General Hospital, Northampton; Northwick Park Hospital, London; Nottingham City Hospital, Nottingham; Queen Alexandra Hospital, Portsmouth; Queen Elizabeth Hospital, Woolwich; Queens Medical Centre, Nottingham; Raigmore Hospital, Inverness; Royal Alexandra Hospital, Brighton; Royal Belfast Hospital for Sick Children, Belfast; Royal Berkshire Hospital, Reading; Royal Children’s Hospital, Aberdeen; Royal Cornwall Hospital, Truro; Royal Devon and Exeter Hospital, Exeter; Royal Edinburgh Hospital for Sick Children, Edinburgh; Royal Free Hospital, London; Royal Liverpool Children’s Hospital, Liverpool; Royal London Hospital, London; Royal Preston Hospital, Preston; Salisbury District General Hospital, Salisbury; Sheffield Children's Hospital, Sheffield; Southampton General Hospital, Southampton; St George's Hospital, London; St Luke’s Hospital, Bradford; St Mary's Hospital, London; St Thomas’ Hospital (Evelina Children’s Hospital), London; Torbay Hospital, Torquay; University Hospital Lewisham, London; University Hospital of North Staffordshire, Stoke On Trent; University Hospital of Wales, Cardiff; West Cumberland Hospital, Whitehaven; Wexham Park, Slough; Whipps Cross Hospital, London; Whittington Hospital, London; Wythenshawe Hospital, Manchester.