Children and resistance to HIV: CHIPS data Dr Katherine Boyd on behalf of Collaborative HIV Paediatric Study (CHIPS) and the UK HIV Drug Resistance Database

Introduction There are over 20 antiretroviral drugs to treat HIV infected children. A lack of age-appropriate formulations and pharmacokinetic data can result in sub-therapeutic concentrations. Poor adherence can be a problem and cause resistance, particularly in adolescence. Objectives: 1) Possible transmission of resistance. 2) Acquired resistance in children after starting ART.

UK HIV Drug Resistance Database Established in 2001 as a central repository of resistance tests carried out as part of routine care in the UK. Contains all routinely-performed (or within PENTA trials) HIV drug resistance tests in the UK, , from all laboratories. Data include some patient demographics, dates and locations of tests, and resistance mutations. Drug susceptibility (using the Stanford HIVdb) and HIV subtype are also available.

CHIPS data A multi-centre cohort study of HIV infected children under care in 59 hospitals in the UK & Ireland since UK children in CHIPS between 1998 and % female, 77% black African, 52% born abroad, 95% with known vertical infection. Matched 710 tests in 389 children: 239 children have 1 test, 77 have 2 tests, 35 have 3 tests, and 38 have four or more tests. Rates of testing consistent across the UK. 2.6% have documented pMTCT.

Use of resistance testing: by previous ART experience* Tests before first reported ART Tests after first reported ART Number of tests (children)65(65)635(336) Age at test (years): Median (IQR) 6.1(1.0, 9.1)10.0(6.0, 13.4) CD4% at test: Median (IQR) 18(12, 24)21(12, 29) Log 10 HIV1-RNA at test (copies/ml): Median (IQR) 5.3(4.8, 5.7)4.3(3.7, 4.9) 43% HIV subtype C, 19% subtype A, and 9% subtype B * ART status can not be defined for 10 tests.

Tests prior to starting ART: by year Starting ART with a resistance test Starting ART without a resistance test % of those starting ART that had a prior test : PENTA 5

ART naïve: Evidence of transmitted drug resistance? Age (yrs) Born abroad? Age (yrs) presented to UK services Mutations* PINRTINNRTI 10.2NoBirth215I 20.9India0.9215I 32.0Portugal2.0184V 215C 215Y 219E 40.4NoBirth184I188L 516.1No2.3 41L 74V 184V 210W 215Y 101E 181C 190A 60.4NoBirth47A 84V 41L 67N 70R 210W 215F 215V 219E * Using Shafer et al. AIDS 2007, Vol. 21. Children with at least 1 major resistance mutation: Overall rate = 6/65 (9%).

Tests after starting ART: by year % of children with test : Child with a resistance test and previous ART Child with one HIV-RNA > 1000 c/ml with previous ART

Major resistance mutations by year in tests after the start of ART* (n=635) PI NRTI NNRTI Any class 36% of children with resistance to NRTIs had mono/dual therapy compared to 13% of those who did not. * Using IAS guidelines Topics in HIV Medicine 2007, Vol. 14.

Prevalence* of resistance to individual drugs in children after the start of ART (n = 336) PI NRTINNRTI Intermediate level resistance High level resistance * Based only on the last resistance test per child

ART class major resistance* in ART experienced children (n=336) Resistance to 0 classes 1 class 2 classes 3 classes * Based only on the last resistance test per child * Using IAS guidelines Topics in HIV Medicine 2007, Vol. 14.

Triple class resistance in ART experienced children In CHIPS, 391 children have had triple class exposure. Of these, 23 (5.9%) have known triple class resistance and 137 (35.0%) have resistance to two ART classes. Median (IQR) age at tests showing… triple class resistance: 10.3 (6.0, 13.3) years. resistance to two ART classes : 9.1 (5.5, 12.7) years Half of those with resistance to at least 2 classes were ≥13 years old.

Discussion and Conclusions: Resistance in ART naïve children There is little use of resistance testing in ART naïve children. Slightly higher use in ART experienced children possibly increasing over time. Possible evidence of some transmitted resistance from mother to child.

Discussion and Conclusions: Resistance after starting ART Resistance to NRTIs may reflect use of mono/dual therapy prior to HAART. Higher resistance to NNRTIs reflects the relatively rapid emergence of resistance to these drugs compared to boosted PIs. Resistance, in particular triple class, will affect future drug choices for adolescents transferring to adult clinics. Low use of T-20 and Raltegravir in children.

Acknowledgements CHIPS centres, staff, and children NSHPC The UK Collaborative Group on HIV drug Resistance