Wide disparity in switch to second-line therapy among children in CHIPS cohort
Polly Clayden, HIV i-Base
Kate Lee from the MRC presented data from the Collaborative HIV Paediatric Study (CHIPS) – a multicentre cohort of HIV positive children receiving care in 39 hospitals across the UK and Ireland since 1996. The CHIPS cohort includes 90% of HIV positive children in the UK and Ireland.
The study investigated characteristics of switch to second-line treatment in children who had initiated therapy HAART naive. This included predictors of earlier switch; CD4 and viral load at switch; and timing of switch with respect to viral load thresholds. Switch was defined as substituting either >/=3 drugs in the regimen or 2 drugs with recorded reason for failure, with viral load >50 copies/mL.
Of a group 595 children initiating therapy HAART naive, 132 (22%) children switched to second line therapy after a median 7.2 years (rate 7.8/100 child-years (CY) [95%CI 6.6-9.2]).
The total population of children was a median age of 4.7 years (IQR: 1.5-8.8 years) with median CD4% 14% (IQR: 8-20.5%), absolute CD4 366 (IQR: 159-700) cells/mm3 and viral load 138,201 (IQR: 123,722-154,373) copies/mL. The median follow up was 3.1 (range: 0-8.2) years. 78% children had had an undetectable viral load <400 copies/mL at any time during first line therapy. The children had received 40 different antiretroviral combinations: 61% had received an NNRTI; 32% a PI; 1% both and 8% NRTIs only.
The investigators reported that the median CD4 count at switch was 485 (IQR: 217-840) cells/mm3 and 20% (IQR: 12-26%) but only 63 (48%) had achieved viral load <400 during first-line therapy.
Viral load at switch was 8,206 copies/mL (IQR: 5,382-12,512) in children who had suppressed on first line vs. 79,569 copies/mL (IQR: 62,127-101,907) in those who had not. The also found that time to switch was longer in those who had suppressed (median >7 vs. 3.1 years respectively, adj HR=0.12 [0.08-0.19]).
Evaluating independent predictors of earlier switch they found: failure to ever achieve undetectable viral load to <400 copies/mL on first line (HR: 7.0 [4.7-9.8], p<0.001); older age at HAART initiation (HR: 1.1[1.0-1.2] per year older, p=0.006); lower CD4% at HAART initiation (HR: 0.87 [0.78-0.97] per 5% higher, p<0.001) and later calendar year at HAART initiation (HR: 1.5 [0.9-3.0] for 2002 vs. 1997-99, p=0.15) were associated.
They reported that sex; current age, viral load or prior adverse events at HAART initiation were not independently associated with earlier switch.
By 3 years after HAART initiation, 14% and 18% of children switched before reaching viral load thresholds of 1000 and 30000 copies/mL respectively (as in the PENPACT 1 trial); 3% & 1% reached thresholds and switched within 6 months with 15% & 3% remaining on 1st-line for >6 months after confirmed viral load >1000 or >30000 copies/mL. Median time to switch after thresholds was 3.3 and 1.0 year respectively.
The investigators noted that children were Switching somewhere between 1000 and 30,000 copies/mL but no clear level. There was No clear threshold being used to trigger switch.
Overall they found a low rate of switching to second line, with children never achieving undetectable viral load switching sooner than those who had; older children switching sooner than younger and children starting HAART more recently or with lower CD4% also switching sooner.
They added that there was little consistency in CD4 and viral load at switch.
Paediatricians seem to be fairly conservative about switching ART for all children, and There is an urgent need for evidence on which to base switching to guide management for the future, they wrote.
It would be wrong to extract from these findings that a childs first line regimen should last for an average of seven years before switching (in those who had ever suppressed) as this will have depended on the childs ability to tolerate a detectable viral load.
This study concludes that paediatricians have been fairly conservative about switching. It was important that there was an analysis by calendar year, as between 1996 and 2000 there were fewer options and more reluctance to switch and this shows a non-statistically significant trend (p=0.15) towards switching at lower viral loads in more recent calendar years. There is also a growing understanding of the implications of resistance (see below).
Several paediatricians have suggested that these results provide additional support for PENPACT 1, which looks at PI vs NNRTI and has a second randomisation looking at switching children at a low viral load (1000 copies/mL) and 1.5 log higher (30,000 copies/mL). This study is now fully enrolled with 260 children.
Lee KJ, Lyall H, Walker AS et al. Wide disparity in switch to second-line therapy in HIV-infected children in CHIPS. 8th International Congress on Drug Therapy in HIV Infection, 12-16 November 2006, Glasgow. Oral abstract PL2.4.