Personalized Therapeutics: HIV Treatment in Adolescents

Abstract

Adolescents infected with human immunodeficiency virus (HIV) represent a heterogeneous group of pubertal children and young adults. Antiretroviral therapy (ART) in adolescents is complex and depends on multiple factors. The continued use of higher (weight-or surface-based) pediatric doses can result in potentially toxic drug exposure, whereas early introduction of lower adult doses can lead to the development of drug resistance and virologic failure. The physiological and psychosocial changes during puberty create strong grounds for an individualized therapeutic approach in HIV-infected adolescents.Despite significant progress in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV) infection, it was estimated that there were 2.3 million children under the age of 15 years with HIV infection in 2006.1 Among those, ~780,000 (600,000-1,000,000) were estimated to be in need of antiretroviral therapy (ART). In the United States and other developed countries, an increasing number of children with perinatally acquired HIV infection are now surviving into adolescence and adulthood. In addition, large numbers of American teenagers continue to acquire HIV infection through sexual contact and intravenous drug use; youths between 13 and 24 years of age account for 15% of the 40,000 new HIV cases per year.2 Based on the strengthening global response to the problem of HIV/AIDS in recent years, the number of adolescents receiving ART worldwide is rapidly increasing.3 Given the growing number of HIV-infected youth with access to ART, a better understanding of the disposition of antiretroviral (ARV) drugs during puberty is urgently needed. The selection of ART dosages for patients in the pubertal stages of maximal growth is left to the provider's discretion, and individual differences in the progression to sexual maturation are often not provided for. However, very few studies have investigated the PK/PD of ARV agents in adolescents and young adults. The PK of abacavir were reported from the PACTG protocols P1018 and P1052;5 , 6 lamivudine and zidovudine data (including data on phosphorylation to the intracellular triphosphate metabolites) were collected in PACTG studies P1012 and P1052;7 lopinavir/ritonavir and saquinavir were studied in PACTG protocol P1038;8 and atazanavir was studied in PACTG protocol 1020A and in Adolescent Medicine Trials Network studies along with tenofovir.5 , 9 The PACTG protocol P1038 and the author's study in children with experience of ARV suggested that the use of high doses of lopinavir/ritonavir might be required for salvage HIV therapy in adolescent patients.8 , 10The Adolescent Medicine Trials Network study by Kiser et al. evaluated the PK of the combined administration of atazanavir/ritonavir and tenofovir in young adults with HIV infection.9 A higher level of tenofovir exposure was expected on the basis of data from healthy volunteers, but this was not seen in HIV-infected subjects, most likely because of a faster tenofovir clearance, as apparent in the h...

Pharmacokinetics of Lopinavir/Ritonavir Crushed Versus Whole Tablets in Children

“…This finding is consistent with higher variability of lopinavir/ritonavir in children and is possibly due to age, physical and sexual maturation and weight differences of the subjects. (25–27) In our study, the decrease in AUC ranged from 5% to as high as 75%. Similarly, decreases in C max and C 12 varied greatly, albeit to a lesser extent than AUC.…”

Drug-Induced liver injury with hypersensitivity features has a better outcome: A single-center experience of 39 children and adolescents

“…However, this study and the preliminary data from DILIN 19 show that children, and particularly adolescents, are at greater risk of developing DILI. 29 Challenges such as fixed drug doses, weight-based or surface-area-based formulations, the immaturity of metabolizing enzymes, and the lack of awareness about the risks of hepatotoxicity in children may be contributing factors. Additionally, interactive toxicities between ATDs 30 and anticonvulsants, such as phenytoin and carbamazepine, 31 might be contributing factors.…”

Adolescent HIV treatment issues in South Africa

“…[6] This heterogeneous group of pubertal children and young adults are more vulnerable and at an increased risk of HIV acquisition. [7] Furthermore, adolescents are less likely to present for testing or be tested for HIV infection. [8] Young women are often diagnosed with HIV after the diagnosis of an unplanned pregnancy, leading to the dual impact of a new diagnosis and an unplanned pregnancy.…”

“…[12] Low pill burden and once-daily treatment regimens with minimal side-effects also impact on long-term compliance. [7] Attention to monitoring adherence and providing ongoing support are key to effective ART.…”