Paediatrics: children are not small (or miniature) adults

14 April 2000. Related: Conference reports, Paediatric care, CROI 7th (Retrovirus) 2000.

Polly Clayden, HIV i-Base.

The current favourite buzz-phrase used to sum up paediatric research and care is ‘children are not small (or miniature) adults’.

Certainly, from a pharmacokinetic point of view, we know that: children’s livers function more efficiently than adults relative to their body weight or surface area; that their total body fluid is relatively higher; that certainly with babies and children under two, gastric acid production is not fully developed and particularly compounded with their differing food requirements this can effect drug absorption and therefore dosing compared to adult patients.

Broad principles and goals of therapy however remain the same for all HIV-infected individuals be they adults, adolescents, children or infants. The latest US Pediatric Guidelines [1] state that ‘Clinical trials of antiretroviral agents in HIV-infected children and the development of drug formulations appropriate for administration to children have often been delayed until after clinical trials in infected adults have been completed and/or the drug has been approved for use among infected adults. However despite these delays, the paucity of paediatric-specific data cannot further delay the development of rational and reasonable treatment guidelines while studies in children are being undertaken.’ This time lag between adults’ and children’s treatment development has often invited criticism, and It comes as no surprise that many of the important clinical issues that we have seen implicated in adult care are frequently found to be also applicable to children. Much of the paediatric-specific data presented at 7th Conference on Retroviruses and Opportunistic Infections bore testimony to this.

Body composition, fat redistribution and lipid levels

Two studies looked at what has been broadly termed lipodystrophy syndrome in adults. One of these looked at changes in regional fat (RFC+) in a group of HIV-infected children using ARV ages 4.3 to 14.9 years ascertained using dual x-ray absorptiometry (DEXA) scans [2]. RFC+ was defined as an increase in truncal fat combined with a decrease in appendicular (arm and leg) fat. Children without these specific body changes (RFC-) were compared at baseline and follow-up.

Of the 32 children studied nine (28%) were RFC+. There were no differences in age, height, weight, total body fat percent or distribution of race, gender or stage of sexual maturation compared to the RFC- group and the interval between DXA scans and length of time on PI-containing regimens were similar in both groups. RFC+ children had significantly lower mean CD4 counts at baseline (167 ± 198 vs. 653 ± 438 cells/mm3, p=0.002) and at follow up (403 ± 208 vs.700 ± 443 cells/mm3, p=0.03) compared to RFC- children. An increase in CD4 count of >25% was associated with RFC. Six out of 9 RFC+ children began PI containing regimens compared to 9 out of 23 RFC-children in the interval between the DXA scans, changing to a PI-containing regimen was not significantly associated with RFC. RFC+ children received seven distinct treatment combinations involving nine medications including five NRTIs, three PIs and one NNRTI. The investigators concluded that a pattern of regional fat distribution previously identified as a risk factor for atherosclerosis is found in HIV-infected children and that treatment related improvements in immune function appear to be related to these changes.

The second study set out to determine whether HIV-infected children treated with ARV therapy including PIs will have different blood lipid levels and body composition compared to those children on PI sparing regimens [3]. Levels of lipids and apolipoprotein B were determined in the fasting state and body composition and fat distribution were determined by anthropometric measurements and DEXA scans. This analysis included 18 children treated with 3-5 ARV agents including at least one PI for a median of 19 months, and 9 treated with 1-2 NRTIs only (non-PI group). The age range of the PI-treated group was 4 to 14 years (median 9 years) and the non-PI 6 to 18 years (median 10 years). The median CD4 count was 858 cells/mm3 in the PI-treated group and 539 cells/mm3 in the non-PI group. 14/17 children in the PI group had plasma RNA levels <50 copies/mL while the median RNA level in the non-PI group was 4,200 copies/mL.

Differences were observed in total and LDL cholesterol levels in the two groups – the median total cholesterol level was 208 mg/dl for the PI-treated children and 144 mg/dl for the non-PI children. LDL cholesterol levels were also higher in the PI group, median PI 124 mg/dl and non-PI 79 mg/dl. Eleven (61%) children in the PI group had total cholesterol levels >200 mg/dl and LDL levels >130 mg/dl, none of the non-PI group demonstrated these elevated levels. Apolipoprotein levels were also higher in the PI group (PI89, n PI68), no differences were observed between the groups in triglyceride, VLDL, HDL, HDL2 and HDL3 levels. Body composition – BMI, waist/hip ratio, and distribution of body fat also was no different between the two groups.

Although metabolic changes occurred in the children studied, anecdotally it is believed that these changes accompanying ARV therapy are less marked in children than in adults. The investigators in the second study noted that ‘The metabolic syndrome that accompanies PI therapy appears to affect children to a lesser degree than adults and/or may require completion of pubertal development before full expression is seen.’No studies addressed the possible role of d4T in metabolic changes that is causing concern amongst adult populations.

Antiretroviral therapy

One dedicated poster session presented results from recent studies reviewing the use of antiretrovirals in treatment of HIV-infected children. Two of these looked at the use of amprenavir in multi-drug regimens in both drug naive and drug-experienced children. The first involved 228 PI-naive (109 children) or PI -experienced children (120 children) with extensive use of NRTIs, with an age range 4 to 18 years, both groups had detectable viral loads [4]. Dosing was 1200mg bid for children 13 years or older and 20mg/kg for those children younger than 13 (or weighing less than 50kg). All 228 children received APV (oral solution was available for those unable to swallow capsules) plus 2 NRTIs, in the NRTI group at least one to which they were naive. At 24 week follow up the NRTI-naive children had a 1.04 log drop in VL and a median CD4 increase of 130 cells/mm3. APV performed poorly in the children with PI-experience and had far less reduction in VL than in the PI-naive group.

The second poster presented the results from a phase II study of APV in antiretroviral-experienced children with HIV infection [5]. It evaluated the use of APV in 40 children (25 PI-naive, 15 PI-experienced) with an age range of 2 to 12 years who were randomised to receive doses of either 20mg/kg bid or 15mg/kg tid APV oral solution in combination with two NRTIs. In addition a very thorough baseline profile was assessed and steady state PK obtained. In the PI-naive group of children VL was maintained <10,000 copies/ml in 62%, the median reduction of VL was a 1.82 log drop. The median increase in CD4 count was similar to the former study (134cells/mm3). PI-experienced subjects showed a minimal response with a median CD4 increase of 51cells/mm3 (intent to treat analyses).

From the results of these two studies it appears that amprenavir performed poorly in a salvage setting with 2 NRTIs and would not be recommend for salvage therapy in PI-experienced children.

ACTG 397 looks at two saquinavir (SGC) containing regimens with the aim to evaluate the tolerability, safety and virologic and immunologic effects of SQV-SGC combination therapy in children [6]. It is an open-label, randomised, two arm study. In arm one subjects receive SQV at 50mg/kg tid plus 2 NRTIs and arm two they receive SQV + NFV plus 1 or 2 NRTIs. Each arm is to enrol 25 children between the ages of 3 and 17 years, at 9.99 so far 51 children had been enrolled and 37 (73%) remain on treatment. No VL data was presented but the regimen so far has been well tolerated.

Of significance this move towards dual PI-containing regimens for paediatric patients in this and other presentations would seem important (see also PK below).

Pharmacokinetics and TDM

There were also a number of studies looking at pharmacokinetics in children, which we reviewed in more detail in our conference report on TDM in DrFax 83 [7]. Several PK studies made recommendations for neonates and babies under two, and several revealed inadequate concentrations of drug using pre-determined dosing levels. With so many obstacles to adherence in babyhood and childhood it seems reasonable to recommend these tests to ensure optimal dosing, the report suggests that ‘With a relatively small HIV-positive population of around 300 children (in the UK) integrating and maintaining optimum dosing for children would eliminate this unnecessary variable.’

Quantitative RNA viral load assays to determine the HIV-status of infants born to infected mothers.

A Brazilian study [8] used a nucleic acid sequence based amplification (NASBA Organon Teknika) performed on 176 HIV exposed children to determine viral load. Results were then compared to clinical outcome and serological tests performed at up to 18months. The infants were divided into 2 groups according to their age at which the first plasma sample was obtained. Group a] < or = 30 days, b] > or = 30 days. In the first group (n= 56) the positive predictive value was 83.3% but for infants over 30 days (n=120) the positive and negative predictive values were 100%.

Another US study [9] compared performance of HIV-1 culture, DNA PCR in infants in a perinatal study PACTG 185. The positive predictive values at six weeks for culture, DNA or RNA were 100%, 92.9%, and 100% respectively. So RNA diagnostic outperformed or equalled the more standard tests for diagnosing perinatal infection.

The choice of RNA appears to be sensitive and specific in early diagnosis of infants, and the Brazilian investigators mentioned that in developing countries such as theirs early diagnosis had many advantages as to costs saved on clinic visits, prophylactic drugs etc performed until the diagnosis of status. They also mentioned the social aspects of a decreased waiting time. Further study for early diagnosis of perinatal HIV is warranted.

Comment

Wide variability in protease inhibitor PK in children (almost invariably towards underdosing) argues strongly for individual titration of these drugs using TDM. Additionally, the use of small doses of ritonavir as a PK enhancer while monitoring with TDM should be explored in children. Such double PI combinations, while common in adults, do not seem to be adequately utilised for this group of patients.

It should also be remembered that children are, of course, growing. Their capacities to absorb and metabolise drugs are therefore changing over time. Regular TDM would seem warranted to ensure correct drug levels as metabolism changes with maturity.

References:

1. Guidelines for use of Antiretroviral Agents in Pediatric HIV Infection, US National Pediatric and Family HIV Resource Centre (NPHRC) et al. January 7 2000
2. Arpadi S et al. Changes in Regional Fat Distribution in HIV-Infected Children. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 65].
3. Melvin A et al. Blood Lipid Levels and Body Composition in HIV-Infected Children Treated with Protease Inhibitors. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 66].
4. Church J et al. A Phase III Study of Amprenavir in Protease-Inhibitor-Naive and Experienced HIV-Infected Children and Adolescents. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 693].
5. Blanche S et al. A Phase II Study of Amprenavir (141W94, AGENERASE) in Antiretroviral-Experienced Children with HIV Infection. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 695].
6. Kline MW et al. A Randomised Trial of Two Saquinavir (SQV-SGC) Containing Regimens in HIV-Infected Children PACTG 397. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 694].
7. Pharmacokinetics, Drug-Drug interactions and Therapeutic drug Monitoring. Simon Collins. Dr Fax #83 pp10. 25.2.00
8. Souza IE et al. Evaluation of plasma viral load for the establishment of the HIV-infection status in Brazilian children born to seropositive women. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 712].
9. Mofenson L et al. Performance characteristics of HIV-1 culture, DNA PCR or quantitative RNA for early diagnosis of perinatal HIV-1 infection. 7th CROI; January 30-February 2, 2000; San Francisco, CA. [Abstract 713].