Stéphane Blanche

Background: Lopinavir/ritonavir (LPV/r) is now the protease inhibitor regimen of choice in the first-line antiretroviral therapy for children 10 copies/mL (4.6–6) and 15% (8–27.5), respectively. HAART included LPV/r and 2 nucleoside reverse-transcriptase inhibitors, mainly lamivudine (3TC), zidovudine, and/or abacavir. The median follow-up period was 36 months (18–72). Less than 50 copies/mL of HIV RNA was observed in 46%, 67%, and 70% of the children at months 6, 9, and 12, respectively. In all, 20 children (46.5%) experienced a VF. The risk factors of primary VF were a young age and a low socioeconomic status. The genotypic resistance test, performed for 18 of 20 children with VF, revealed 1 LPV/r-resistant virus and protease inhibitor-related major mutations without LPV/r resistance in 2 other children. Of the 18 children with VF, 15 received a 3TC-based HAART: 12 of 15 (80%) harbored a 3TC-resistant virus. No virus resistant to zidovudine or abacavir was found. Conclusion: In all, 70% of HAART-naive children had virologic success at month 12. The selection of LPV-resistant strains was a rare event. A high rate of selection of 3TC-mutations strengthens the recommendation to prefer a first-line 3TC-sparing regimen, particularly for children with risk factors of poor adherence.

To assess pharmacokinetics, safety and efficacy of darunavir/ritonavir (DRV/r) and optimized background regimen in treatment-experienced patients (6-17 years).Forty-eight-week, open-label, two-part, phase II study.In part I, 44 patients were randomized (1: 1 ratio) to receive a body weight-adjusted, adult-equivalent dose (group A) or a 20-33% higher DRV/r twice daily (b.i.d.) dose (group B). Pharmacokinetics, safety and efficacy were assessed following 2-week dosing (part I), which determined dosing for part II (evaluated 48-week safety and efficacy).In part I, both groups met the protocol-specified criteria for pharmacokinetics and showed favorable tolerability and efficacy. The following body-weight doses were selected: DRV/r 375/50 mg b.i.d. (20- or =40 kg); these gave an AUC24h, C0h and Cmax of 102, 114 and 112%, respectively, versus the corresponding mean adult pharmacokinetic parameter. In part II, 80 patients received DRV/r (median age: 14 years, mean baseline HIV-1 RNA: 4.64 log(10)copies/ml). One patient (1%) discontinued (treatment-unrelated grade 3 anxiety). An abnormal mean baseline triglyceride level was normalized at 48 weeks (P < 0.01). At week 48, 65% had at least 1.0 log(10)HIV-1 RNA reduction; 59 and 48% achieved HIV-1 RNA less than 400 and less than 50 copies/ml, respectively (time-to-loss-of-virologic response). Mean age-adjusted weight z-score increased by 0.2 (P = 0.003).In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population.

A single-center cross sectional evaluation of β-2 microglobinuria as a marker of proximal renal tubule damage in 92 HIV-infected children showed that tenofovir treatment was significantly associated with very high abnormal values. In view of the very long duration of treatments for HIV infection, their possible consequences for the child's growing body should be carefully evaluated.

Background. Some children who are infected with human immunodeficiency virus type 1 (HIV-1) during the perinatal period remain asymptomatic for very

Clinical and biological observations of mitochondrial dysfunction in children exposed to zidovudine (azidothymidine, AZT) during the perinatal period rapidly followed similar observations in animal experiments. To date, two different disorders have been identified. The first, asymptomatic hyperlactatemia, is observed during treatment in one third of exposed newborns, and is reversible with treatment cessation. In rare cases, it is associated with symptomatic acidosis. Regression may be slow, taking up to several months after the end of the treatment. The long-term clinical consequences of this biochemical disturbance are unknown. The second disorder involves severe neurological symptoms, which become clinically detectable during the first 2 years of life. These symptoms are associated with a series of biochemical and ultrastructural changes consistent with persistent mitochondrial dysfunction. This latter phenomenon is rare, and affects only 0.3–0.5% of exposed children in the French pediatric cohort, in which observations continue. Despite initial controversy, several similar observations in other cohorts have since confirmed its occurrence. The pathophysiology of these two mitochondrial dysfunctions may differ. Continued efforts to identify and understand clinical mitochondrial toxicities are essential, given the intensification and diversification of perinatal prophylaxis strategies, and the number of pregnant women potentially involved. Environ. Mol. Mutagen.

Background: Pediatric experience with atazanavir combined with antiretroviral drugs administered once daily is very limited. Objective: The objective of this prospective, single-center observation study was to evaluate efficacy and tolerance of once-a-day ritonavir-boosted atazanavir, including treatment. Results: Antiretroviral treatment of 23 children and adolescents with a median age of 16 years (range, 10–19 years) was changed to a single daily dose of a combination of ritonavir-boosted atazanavir and 2 other nucleoside or nonnucleoside analogs. The single daily dosing was expected to improve adherence to treatment. The mean follow-up period was 12 months (range, 6–17 months). At the time of the treatment switch, the previous treatment had been effective in 11 children (plasma viral load [pVL] 50 copies/mL). None of the viral genotypes had resistance to atazanavir. The susceptibility score for the drugs used in combination with atazanavir (GSS) was at least 1.5 in 12 of 20 children. The atazanavir dose was 300 mg per day for children weighing more than 50 kg and 200 mg per day for children weighing 30 to 50 kg, in all cases associated with 100 mg ritonavir. During follow up, the mean atazanavir plasma concentration at 12 to 15 hours was 2.18 ± 1.19 mg/L. Tolerance was good in most patients, but 4 children chose to stop treatment because of icterus (n = 2) or persistent nausea and vomiting (n = 2). In 6 of the 12 children in whom treatment was not virologically effective before the switch, pVL was below 50 copies/mL after 1 to 3 months of treatment. Poor compliance and virologic failure persisted in the other 6 children. Seven of the 11 children with good virologic control before the switch continued to have undetectable pVL but 4 experienced virologic failure after 1, 1, 3 or 12 months of treatment despite good compliance. Insufficient antiviral potency of associated drugs could have been the cause of 2 of these 4 unexpected virologic failures. Conclusion: In these children with extensive previous treatment, the change to a once-daily treatment, including ritonavir-boosted atazanavir, was associated with a significant risk of virologic failure.

Pediatric HIV-1 infections are still being diagnosed in France, despite the efficacy of prophylactic treatment to prevent mother-to-child transmission. To describe the characteristics and mode of infection of these children, we retrospectively analysed data of 59 children diagnosed with the HIV-1 infection between January 2000 and June 2005 in a Parisian university hospital. Twenty of these children had been born in France, and none had received appropriate prophylaxis (insufficient, not taken or given too late). Six received no preventive treatment due to failures in screening: three mothers were HIV-seronegative at the start of pregnancy and no test was carried out for the other three. At diagnosis, four had a severe immune deficiency (CD4 cells <15%). The 39 children born abroad were diagnosed at a median age of 3 years (range: 3 months–16 years), sometimes several years after their arrival in France. The clinical, virological and immunological status of these children was poorer than that of the children born in France: 18 had less than 15% CD4 cells. In contrast, the response to treatment of the children born in France was not as good as that of the children born abroad. The HIV-1 screening and prevention programme for pregnant women could be improved. Some children infected following the failure of prevention are at high risk of subsequent treatment failure. HIV-1 infection should be taken into consideration in children born in countries with a high prevalence of HIV, even if they have been living in France for several years and present no symptoms.