A French study of 69 children treated with the protease inhibitor (PI) lopinavir/ritonavir (Kaletra) found that two-thirds of children who had failed on other PIs also failed to achieve undetectable viral loads on Kaletra. Furthermore, three-quarters of those who failed acquired new lopinavir resistance mutations. In contrast only two PI-naïve children failed, and neither did so having acquired any PI resistance mutations. The study was reported in the October 1st edition of the Journal of Acquired Immune Deficiency Syndromes.
The study authors conclude that therapeutic drug monitoring and dose adjustments may be needed for children treated with lopinavir who have moderate pre-existing PI resistance.
The children were a group who were treated with lopinavir, prior to it receiving an EU licence, via a ‘temporary authorisation for use’ between March 2000 and April 2001. They were followed up for 18 months.
The mean age of the children was 10.3, the youngest being 5.5 years old and the oldest 15. Forty-eight of the children (70%) had previously taken PI-based therapy.
A number of the PI-naïve children had pre-existing polymorphisms in their HIV protease which convey secondary resistance to lopinavir; these mutations do not cause resistance themselves but strengthen resistance when other mutations are present. The PI-naïve children had an average of one of these secondary mutations each, and none had more than three.
In contrast the PI-experienced children carried an average of 2.5 PI resistance mutations, with a maximum of eight, and these included ones conveying resistance to lopinavir, including 10-40% of them carrying one or more of the mutations at positions 46, 54, 82, 84 and 90 of the HIV protease enzyme.
There were big differences between the virological response rates of the PI-naïve and PI-experienced children. All but two (92%) of the PI-naïve children remained under 400 copies/ml by 18 months, and 75% under 50 copies/ml. Only 39% of PI-experienced children had a viral load under 400 at 18 months and 35% under 50.
Only 20% of children with four or more lopinavir mutations at baseline remained virologically suppressed at 18 months compared with 85% of those with less than four. All children with more than five lopinavir mutations had failed by nine months, though this was a small group (seven children). Having four or more lopinavir resistance mutations at baseline carried an eightfold greater risk of failure.
Twenty-two of the children who failed virologically had resistance tests done - both of the naïve children who failed and 20 of the 25 PI-experienced children. It was found that neither PI-naïve child who failed had acquired any lopinavir mutations.
In contrast 17 of the 20 PI-experienced children who failed acquired new lopinavir resistance mutations, the most common single mutation being at position 46 of the protease enzyme. Nearly a third (seven) of the PI-experienced children who failed acquired the same five lopinavir resistance mutations at positions 46, 50, 82, 84 and 90 – and these were not the children who had already got at least one of these mutations at baseline.
The clinical ‘cut-off’ point for lopinavir-related treatment failure, i.e. the time when treatment change is considered, was considered by this research group to be a viral load of 10,000 copies/ml in the case of lopinavir-based regimens. Nonetheless six of the children who acquired lopinavir resistance mutations did so with a viral load under 10,000 copies/ml.
The authors comment that a lower ‘cut-off’ point for treatment failure should be used in children.
The only other predictor of failure was the ‘genotypic inhibitory quotient’ (GIQ). A GIQ under one in the PI-experienced children carried a fourfold greater risk of failure.
The GIQ is the ratio of lopinavir peak concentrations (Cmax) to the number of resistance mutations correlalted with lopinavir resistance, and represents the degree to which lopinavir concentrations fell short of the level need to suppress a patient’s individual level of lopinavir resistance. The study authors comment that upward dose adjustment should be considered for children with moderate baseline lopinavir resistance in order to maximise the GIQ and minimise the risk of acquiring more resistance.
Delaugerre C et al. Predictive factors of virologic success in HIV-1 infected children treated with lopinavir/ritonavir. J Acquir Immune Defic Syndr 37: 1269-1275, 2004.