Effect of specific ART drugs on lipid changes and the need for lipid management in children with HIV.

BACKGROUND: We investigated the effects of individual antiretrovirals on lipids in HIV-infected children and the proportion potentially eligible for dietary or pharmacologic intervention. METHODS: St Mary's and Great Ormond Street Hospital's, London, United Kingdom, patients between 1995 and 2007 were included. Associations between lipids (millimoles per liter) and specific antiretroviral therapy were assessed using mixed-effects models adjusted for confounders. Children eligible for lipid-lowering management were assessed according to American Academy of Pediatric criteria [low-density lipoprotein (LDL) > 190 mg/dL or 4.9 mmol/L for children with no known cardiovascular disease risk factors or LDL > 160 mg/dL or 4.1 mmol/L for children with 2 or more cardiovascular disease risk factors]. RESULTS: Four hundred forty-nine children had median 4.5-year follow-up. On average, antiretroviral therapy-naive children had normal lipids except for low high-density lipoprotein cholesterol (HDL) (median 0.8). All cholesterol subsets were elevated for the 4 drugs assessed. Protease inhibitors had greater rises in total cholesterol with the maximal non-HDL rise for lopinavir/ritonavir at 4+ years of exposure, 0.8 (0.57-1.03). The nonnucleoside reverse transcriptase inhibitors also raised non-HDL, but this was associated with additional clinically significant increases in HDL. Nevirapine raised non-HDL by 0.38 (0.09-0.31) at 2-3 years and HDL by 0.34 (0.28-0.41). Efavirenz raised non-HDL by 0.2 (0.09-0.31) and HDL by 0.12 (0.08-0.17) at 1 year. Ten percent had LDL above the 95th percentile, but only 3 met the 4.9 cutoff for pharmacologic intervention. CONCLUSIONS: Intervention strategies (dietary and exercise advice, treatment switching, and pharmacotherapy) are required for persistent hyperlipidemia and should be assessed in randomized control trials.

PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infection.

PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: 'When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. 'What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained.

Morbidity, mortality, and response to treatment by children in the United Kingdom and Ireland with perinatally acquired HIV infection during 1996-2006: planning for teenage and adult care.

BACKGROUND: Recent evidence suggests that decreases in morbidity and mortality in cohorts of adults infected with human immunodeficiency virus (HIV) are showing signs of reversal. We describe changes over time in these characteristics and in the response to treatment among children in the United Kingdom and Ireland with perinatally acquired HIV infection, many of whom are now adolescents. METHODS: We analyzed prospective cohort data reported to the National Study of HIV in Pregnancy and Childhood (NSHPC) and the Collaborative HIV Paediatric Study. RESULTS: By mid 2006, 1441 HIV-infected children were reported to NSHPC; 40% were > or = 10 years old at their most recent follow-up visit, and 34% were receiving care outside London. The proportion of children born abroad increased from 24% during 1994-1996 to 64% during 2003-2006. The percentage of total child time during which children received highly active antiretroviral therapy (HAART) increased from 36% during 1997-1999 to 61% during 2000-2002 and 63% during 2003-2006. Of children who were naive to antiretroviral therapy at the start of HAART, the percentage with an HIV-1 RNA load of < 400 copies/mL after 12 months increased from 52% during 1997-1999 to 79% during 2003-2006. In multivariate analysis, only calendar time predicted virological response, whereas both younger age and lower CD4 cell percentage at HAART initiation predicted increases of > 10% in the CD4 cell percentage. A total of 31% of children aged 5-14 years and 38% aged > or = 15 years at their most recent follow-up visit had been exposed to drugs from each of the 3 main HAART classes. The rate of AIDS and mortality combined decreased from 13.3 cases per 100 person-years before 1997 to 3.1 and 2.5 cases per 100 person-years, respectively, during 2000-2002 and 2003-2006; rates of hospital admission also declined during this interval. Of 18 children known to have died since 2003, 9 died within 1 month after presentation. CONCLUSIONS: Morbidity and mortality rates among HIV-infected children continue to decrease over time. Because these children are increasingly dispersed outside London, specialist care is now provided in national clinical networks. Transition pathways to adolescent and adult services and long-term observation to monitor the effects of prolonged exposure to both HIV and HAART are required.

Underdosing of antiretrovirals in UK and Irish children with HIV as an example of problems in prescribing medicines to children, 1997-2005: cohort study.

OBJECTIVE: To measure the extent of underdosing of antiretroviral drugs in children. DESIGN: Multicentre cohort study. SETTING: Clinical centres in hospitals in the United Kingdom and Ireland in the collaborative HIV paediatric study (CHIPS). PARTICIPANTS: 615 HIV infected children aged 2-12 years receiving antiretrovirals. MAIN OUTCOME MEASURES: Doses relative to weight and height compared with current recommended doses in 2004 European guidelines. RESULTS: The CHIPS cohort of 934 children comprises 80% of diagnosed HIV infected children in the UK and Ireland between January 1997 and March 2005, of which 66% (615) aged 2-12 years were prescribed antiretrovirals. Actual doses standardised to weight or surface area varied widely across individual drugs, antiretroviral class, and calendar time, with children underdosed (prescribed less than 90% of current recommended doses) from 6-62% child time at risk. Three serious issues in prescribing antiretrovirals, which may also be relevant to paediatric prescribing in general, were identified. Firstly, dosing was inadequate before incorrect recommendations at licensing were later revised when important pharmacokinetic results emerged. Secondly, guidelines stating dosage alternatives (by weight/surface area) for the same drug led to different and inconsistent doses. And, thirdly, ongoing growth was not adjusted for. CONCLUSIONS: Largely inadvertently, HIV infected children in the United Kingdom and Ireland have been underdosed with antiretrovirals, highlighting problems applicable throughout paediatric prescribing.

Children with HIV: improved mortality and morbidity with combination antiretroviral therapy.

PURPOSE OF REVIEW: Advances in the management of children with vertical HIV-1 infection in the developing and developed worlds are discussed in reference to literature published in 2003/4. Studies in mother-to-child transmission are beyond the scope of this review. RECENT FINDINGS: Improvements in mortality and morbidity from HIV-1 infection following combination antiretroviral therapy are extremely encouraging. There is an increase in the understanding of the immune response to HIV-1 in infants and children and a possible future role for immunomodulatory therapies. Preliminary data are available on the timing of initiation of antiretroviral therapy, the optimization of drug combinations and the clinical interpretation of genotypic resistance testing and therapeutic drug monitoring. Evidence is emerging that early antiretroviral therapy can protect the central nervous system in infants. In resource-limited settings, mortality and morbidity remain extremely high but low-cost health interventions such as prophylactic co-trimoxazole can reduce mortality prior to the expansion of antiretroviral therapy programmes. SUMMARY: Further randomized controlled trials assessing antiretroviral therapy combinations with a sustained virological/immunological response with minimal toxicities are required. The roles of therapeutic drug monitoring and resistance testing require further elucidation. The expansion of antiretroviral therapy programmes is essential for children with HIV living in resource-limited settings.