Paediatric drug development and evaluation: Existing challenges and recommendations.

Despite various international regulatory initiatives over the last 20 years, many challenges remain in the field of paediatric drug development and evaluation. Indeed, drug research and development is still focused essentially on adult indications, thereby excluding many paediatric patients, limiting the feasibility of trials and favouring competing developments. Off-label prescribing persists and the development of age-appropriate dosage forms for children remains limited. Against this background, the members of this panel (TR) recommend the launch of multi-partner exchange forums on specific topics in order to focus new drug research and development on the real, unmet medical needs of children and adolescents, and in keeping with the underlying mechanisms of action. Scientific information sharing and cooperation between stakeholders are also essential for defining reference evaluation methods in each medical field. These forums can be organised through existing paediatric facilities and research networks at the French and European level. The latter are specifically dedicated to paediatric research and can facilitate clinical trial implementation and patient enrolment. Moreover, specific grants and public/private partnerships are still needed to support studies on the repositioning of drugs in paediatric indications, and pharmacokinetic studies aimed at defining appropriate dosages. The development of new pharmaceutical forms, better suited for paediatric use, and the promotion of resulting innovations will stimulate future investments. Initiatives to gather observational safety and efficacy data following off-label and/or derogatory early access should also be encouraged to compensate for the lack of information available in these situations. Finally, the creation of Ethics Committees (EC) with a specific "mother-child" advisory expertise should be promoted to ensure that the current regulation (Jardé law in France) is implemented whilst also taking into account the paediatric specificities in medical trials.

Interruption of cART in clinical practice is associated with an increase in the long-term risk of subsequent immunosuppression in HIV-1-infected children.

BACKGROUND: Antiretroviral treatment interruption (TI) is not recommended in HIV-infected children. We aimed to evaluate the context and consequences of TI in clinical practice. METHODS: We investigated the probability and risk factors of a first TI in the 483 children treated with combined ART (cART) in the ANRS French national pediatric cohort. Immunologic and virologic outcomes were compared between patients with TI (TI group) and those on continuous treatment (matched control group), from a baseline defined as the age at first interruption for the TI child and the corresponding age for the control child. RESULTS: At least one TI ≥ 3 months occurred in 42.4% of patients, at a median age of 8.0 years, for a median duration of 12.1 months. After cART initiation, the risk of TI was 7.0% (5.0-9.6) at 1 year and 30.3% (26.1-35.0) at 5 years and was higher for children starting treatment before 2000 and for children starting cART before 6 months of age. AIDS-free survival was similar, but severe immunosuppression occurred earlier in the TI group than in the control group (adjusted HR = 3.1; 1.0-9.1; P = 0.04). Four years after baseline, the proportion of patients with CD4% ≥ 25% was lower in the TI group than in the control group (52.0% vs. 72.0%; P < 0.01), even among children restarting cART at least 6 months earlier (aRR = 0.5; 0.3-0.9; P = 0.03). CONCLUSIONS: The risk of TI in clinical practice has decreased but remains high. In intent-to-treat analysis, TI was associated with a greater risk of subsequent immunosuppression, even after cART resumption.

A three-source capture-recapture estimate of the number of new HIV diagnoses in children in France from 2003-2006 with multiple imputation of a variable of heterogeneous catchability.

BACKGROUND: Nearly all HIV infections in children worldwide are acquired through mother-to-child transmission (MTCT) during pregnancy, labour, delivery or breastfeeding. The objective of our study was to estimate the number and rate of new HIV diagnoses in children less than 13 years of age in mainland France from 2003-2006. METHODS: We performed a capture-recapture analysis based on three sources of information: the mandatory HIV case reporting (DOVIH), the French Perinatal Cohort (ANRS-EPF) and a laboratory-based surveillance of HIV (LaboVIH). The missing values of a variable of heterogeneous catchability were estimated through multiple imputation. Log-linear modelling provided estimates of the number of new HIV infections in children, taking into account dependencies between sources and variables of heterogeneous catchability. RESULTS: The three sources observed 216 new HIV diagnoses after record-linkage. The number of new HIV diagnoses in children was estimated at 387 (95%CI [271-503]) from 2003-2006, among whom 60% were born abroad. The estimated rate of new HIV diagnoses in children in mainland France was 9.1 per million in 2006 and was 38 times higher in children born abroad than in those born in France. The estimated completeness of the three sources combined was 55.8% (95% CI [42.9 - 79.7]) and varied according to the source; the completeness of DOVIH (28.4%) and ANRS-EPF (26.1%) were lower than that of LaboVIH (33.3%). CONCLUSION: Our study provided, for the first time, an estimated annual rate of new HIV diagnoses in children under 13 years old in mainland France. A more systematic HIV screening of pregnant women that is repeated during pregnancy among women likely to engage in risky behaviour is needed to optimise the prevention of MTCT. HIV screening for children who migrate from countries with high HIV prevalence to France could be recommended to facilitate early diagnosis and treatment.

Population pharmacokinetics of atazanavir/ritonavir in HIV-1-infected children and adolescents.

AIMS: To investigate atazanavir (ATV) population pharmacokinetics in children and adolescents, establish factors that influence ATV pharmacokinetics and investigate the ATV exposure after recommended doses. METHODS: Atazanavir concentrations were measured in 51 children/adolescents during a mean therapeutic monitoring follow up of 6.6 months. A total of 151 ATV plasma concentrations were obtained, and a population pharmacokinetic model was developed with NONMEM. Patients received ATV alone or boosted with ritonavir. RESULTS: Atazanavir pharmacokinetics was best described by a one-compartment model with first-order absorption and elimination. The effect of bodyweight was added on both apparent elimination clearance (CL/F) and volume of distribution using allometric scaling. Atazanavir CL/F was reduced by ritonavir by 45%. Tenofovir disoproxil fumarate (TDF) co-medication (300 mg) increased significantly by 25% the atazanavir/ritonavir (ATV/r) CL/F. Mean ATV/r CL/F values with or without TDF were 8.9 and 7.1 L h(-1) (70 kg)(-1), respectively. With the recommended 250/100 mg and 300/100 mg ATV/r doses, the exposure was higher than the mean adult steady-state exposure in the bodyweight range of 32-50 kg. CONCLUSIONS: To target the mean adult exposure, children should receive the following once-daily ATV/r dose: 200/100 mg from 25 to 39 kg, 250/100 mg from 39 to 50 kg and 300/100 mg above 50 kg. When 300 mg TDF is co-administered, children should receive (ATV/r) at 250/100 mg between 35 and 39 kg, then 300/100 mg over 39 kg.

[Prophylaxis for contacts of an index case of hepatitis A: immunoglobulins or vaccination?]. / Prophylaxie autour d'un cas index d'hépatite A: immunoglobulines ou vaccination?

France has changed from a country where hepatitis A is endemic to one where residents are at risk of hepatitis A infection: in 20 years, the seroprevalence in 20-year-olds has fallen from 50% to less than 10%. Prophylaxis for close contacts of an index case has therefore become a major problem because their risk of hepatitis A is high. Polyvalent immunoglobulins are recommended in several countries, but no immunoglobulins are approved for this indication in France. Immunoglobulins are also expensive and only slightly efficacious. A vaccine against hepatitis A administered to young children or adolescents can break the epidemic chain and protect adults very effectively by limiting virus circulation. Many countries propose early vaccination to at-risk contacts, with vaccination generally advised within a week of the initial infectious contact. Although more specific and more plentiful data are still necessary before this recommendation can be generalized, it must be taken into account. This medical decision should thus be made on an individualized basis after discussion between the physician and family about the risk.