Octavio Ramilo
In view of the number of children that have already developed resistance to current PIs, the difficulties associated with currently available formulations, and the recent availability of an expanded access programme in Europe, we wanted to include a presentation in the meeting from an independent investigator with experience of lopinavir/r in a paediatric setting.
Paediatric M98-940 study
The objectives of ths Phase I/II dose-ranging international paediatric study were to evaluate the safety, tolerability and the antiviral activity of lopinavir/ritonavir in combination. This combination is also referred to as ABT-378/r or the trade name Kaletra and is available as liquid formulation for HIV infected children.
The ratio of lopinavir to ritonavir (4:1) is the same in both the paediatric and adult formulations. The pharmacokinetic enhancement from ritonavir increases the peak levels, trough levels and total exposure (area under the curve, AUC), and a prolonged dosing half-life allows a cushion period for some flexibility from a strict Q12H dosing regimen. The ritonavir dose in this formulation is not being used for an antiretroviral effect.
For the entry criteria in the paediatric study we convinced Abbott to be quite open and the children were between three months and twelve years of age. They had to have detectable plasma HIV RNA, and be NNRTI-naive but there were no limitations in terms of CD4 count or other previous treatments.
Children were considered treatment-naive if they had less than three months of therapy or less than one week of 3TC - otherwise they were considered experienced. The regimens chosen were based on the previous experience with adults.
Treatment-naive children received lopinavir/r plus d4T and 3TC. Experienced children received lopinavir/r plus nevirapine and either one or two NRTIs chosen by the individual investigators. The two doses were chosen to achieve the same drug exposure as in adults with a standard 400mg/100mg dose. Children were randomised to either 230/57.5mg/m2 lopinavir/r every 12 hours or 300/75 mg/m2 lopinavir/r. They were also stratified to age (<2 yo and >2 yo) and therapy (experienced or naive).
After half of the children in these groups received at least three weeks of therapy there was an interim analysis for safety, tolerability and efficacy. At that time it was found that both groups had the same tolerability and the same antiviral efficacy. Because of previous results in adults, and a concern for lack of adequate potency, the decision was made to choose the higher dose. The baseline characteristics are shown in Figures 1 and 2.
In contrast to most adult studies which usually have at least 70% males, we had a slightly higher number of girls. There was a wide range of viral load between 2.6 and 7 log (10 million copies/ml). The mean viral load was statistically significantly higher in the naive group (4.9 vs 4.5 logs) and this was also reflected in the difference between CD4 percentage (21.6% vs 26.3% respectively).
The majority of the 56 experienced children had been exposed to AZT/3TC. Children with PI experience had been exposed to most regimens, including abacavir. Almost a third of the PI-experienced patients had used more than one PI.
Approximately half the children were included in the PK analysis including 13 patients under two years of age. Interestingly there was no association between age and drug levels or clearance.
We learned quite rapidly, and this was confirmed with efavirenz in adults, that NNRTIs induce the metabolism of lopinavir/r. So children that got nevirapine in combination with the low or the high dose of lopinavir/r had decreased PK parameters, with trough concentrations that were down by 30% to 40%.
If you use the low dose without nevirapine you get approximately the same drug levels as adults and if you need to use nevirapine then you probably have to jump up to the higher dose. Based on these findings the FDA approved this agent and they recommended an initial dosing in mg/kg which is approximately equivalent to the lower dose evaluated in the study 230/57.5mg/m2 lopinavir/r BID, however this is currently being revised. Personally, in view of the good tolerability and in an attempt to optimise its antiviral activity in treatment-experienced children I would prefer to use the higher dose (300/75 mg/m2 BID) evaluated in the study.
| Fig.1 - Baseline demographics |
Fig.2 - Baseline characteristics |
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Click on slide for a larger view |
Safety and side-effects
Figure 3. M98-940 - adverse events |
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Of a hundred children enrolled in the trial
there were only two discontinuations. One occurred in the first 24 weeks, a five year old child in Panama, who developed lymphoma in the first month of therapy and for that reason the drugs had to be stopped. Although he received chemotherapy he did not survive more than two weeks. The other discontinuation, and this one is related to the study drug, occurred in South Africa and was a child who developed pancreatitis. This child had elevated amylase before enrolling on the trial.
Figure 3 shows a summary of all the adverse events of at least moderate severity of up to week 48 which were remarkably low - single cases of pancreatitis, hepatomegaly, some vomiting, rash and fever.
It was interesting that we had only one child that complained about the flavour as reported in the adverse events section, who was one of my patients, but she did not stop taking it.
Grade 3-4 laboratory abnormalities are
shown in Figure 4. Some of them reflect some of the baseline characteristics - like the child with lymphoma had neutropenia. Two children had to stop therapy: one because of an increase in ALT and one because of an increase in amylase. All the children with increases in amylase also
| Figure 4. M98-940 - Grade 3-4 lab abnormalities |
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had increased baseline amylase and the majority of these children were from Panama and South Africa with advanced
disease.
With cholesterol levels, three children went above 300 mg/dL. Two of them had baseline cholesterol of about 300 mg/dL. One went up to 325 mg/dL and then became normal. The impact on the lipid metabolism is one aspect that we definitely need to learn more about - but these results were definitely much better in terms of the laboratory abnormalities than those seen in adults.
Virological results
| Figure 5. % <400 stratified by baseline viral load |
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In the first three to eight weeks there
were similar results between the naive and experienced children, but we then saw a trend that becomes very clear by week twelve as PI-experienced children were not responding as well as the others.
By
week 48 (ITT analysis),
84% of
treatment-
naive children had viral load reductions to <400 copies/mL. This was 88% among those who were nucleoside-experienced and 58% among those who were PI-experienced. Remember though that a third of these kids have used at least two PIs previously. When we look at the data to <50 copies/mL the results were 69%, 71% and 54% in these three groups respectively, and this is still very
impressive.
The response <400 copies (ITT analysis) was analysed on the basis of the baseline viral load in four groups:
| <
50,000 |
85% |
n=52 |
|
50-100,000 |
100% |
n=9
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100-250,000 |
58% |
n=20
|
| >250,000 |
79% |
n=19 |
| Figure 6. M98-940 - CD4 response |
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| Click on slide for a larger view |
Figure 5 shows that with lower viral loads the response occurs very rapidly. It took longer to get <400 copies/mL for children with a baseline >100,000 copies/mL but still the percentages were very good. Overall there was a trend suggesting a lower viral load at baseline predicted a greater likelihood for achieving viral loads <400 copies/mL.
Conclusion
Based on the current data we concluded that the liquid formulation of lopinavir/r appears to be safe and well tolerated in HIV infected children.
We only had one drug related discontinuation, a few adverse events and three or four laboratory abnormalities. Lopinavir/r appears to demonstrate a substantial viral efficacy in both naive and experienced paediatric subjects. According to the intent-to-treat analysis 84% of the naive and 75% of the experienced achieved less than 400 copies/mL.
Dr Octavio Ramilo is currently Associate Professor of Paediatrics
(Division Paediatric Infectious Disease) and Microbiology and Attending Physician
at the Children«s Medical Center, Dallas, Texas. He trained and worked originally
in Madrid and has a Paediatric Infectious Disease Fellowship at the University
of Texas Southwestern Medical Center, Dallas, Texas.
octavio.ramilo@utsouthwestern.edu
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