Introduction

Human immunodeficiency virus (HIV) infection represents one of the most serious pediatric diseases globally, with an estimated 3.4 million children living with HIV on our planet. The majority of HIV infection among children are acquired through mother-to-child transmission (MTCT) of the virus from women with HIV during pregnancy, delivery, and breastfeeding. In 1990, the landmark Pediatric AIDS Clinical Trials Group 076 study demonstrated that the antiretroviral (ARV) drug zidovudine (AZT) administered to the mother and infant around delivery significantly reduced MTCT. Since then, the use of antiretroviral therapy (ART) during pregnancy, delivery, and postpartum has become the widespread method of the prevention of MTCT (PMTCT). Such unique and unprecedented pharmacologic intervention has been shown to be highly efficient by decreasing the natural rates of MTCT from 30% to 40% to less than 2%.

Currently available ART uses 5 major classes of ARV drugs: nucleoside/nucleotide analogue reverse transcriptase inhibitors (NRTIs/NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry and fusion inhibitors, and integrase inhibitors. The combination ART, also defined as highly active ART, is comprised of 3 ARV drugs from at least 2 major classes to achieve maximal suppression of HIV replication and preservation of immune function affected by HIV disease. Another major benefit of ART is its capacity to reduce the transmission of the virus from one person to another, including the prevention of vertical transmission of HIV from the infected mother to her fetus, newborn child, and infant.

In the countries with guaranteed access to ARV drugs, the number of perinatally acquired pediatric HIV infections is very low and is limited to cases of missed opportunities for the timely identification of HIV, lack of prenatal care, and poor adherence to ARV prophylaxis. In resource-limited settings, which are most heavily affected by the HIV epidemic, the major barriers to effective PMTCT are the lack of adequate prenatal care, lack of HIV testing, limited access to ART, and the need for continued breastfeeding to assure infant’s survival. Despite ongoing efforts to guarantee universal access to PMTCT in the world, the World Health Organization (WHO) reports that approximately half (48% [44%–54%]) of pregnant women living with HIV currently receive ARV prophylaxis for MTCT. Because of the limited access to universal diagnostics and PMTCT, the WHO estimates that 1000 children continue to be infected with HIV each day, with most new cases (97%) occurring in middle- and low-income countries. In addition to perinatally infected children, approximately 2520 new HIV infections per day occur through horizontal transmission in adolescents who are 15 to 24 years of age, with almost half (48%) of the cases among adolescent girls, creating the potential for continued MTCT.

With the ongoing epidemic of pediatric HIV infection in the world, the delivery of efficient ART to children and adolescents is crucial to saving and improving the lives of millions of children worldwide. Per WHO estimates, without therapeutic intervention approximately one-third of the infected infants will die by 1 year of age and about half will die by 2 years of age. ART has been demonstrated to significantly decrease HIV-associated morbidity and mortality, assure normal growth and development, and improve survival and quality of life in children and adolescents.

Following the adult ART development, the treatment of pediatric HIV infection has evolved from monotherapy with AZT to dual therapy with NRTIs and subsequently to multi-drug therapy involving a combination of 3 or more ARV drugs. The pathogenesis and the general virologic and immunologic principles of HIV generates an infectious inflammatory process that is similar in adults and children infected with HIV. However, the important etiologic, physiologic, psychological, and social differences between children and adults create a unique consideration for ART in pediatric patients.

Early initiation of ART in children allows achieving maximal suppression of HIV replication, to preserve immunologic function, and to prevent disease progression while allowing for normal growth and development. The immunologic outcome (activation and suppression of the CD4+ cell count) of HIV infection is closely related to the child’s development and creates age-specific parameters for the evaluation of therapeutic response to ART in pediatric HIV disease. In addition to the changes in immunologic response to the HIV infection, the development and maturation of organ systems involved in drug absorption, distribution, metabolism, and elimination determine significant changes in the pharmacokinetics (PK) of ARV drugs throughout childhood. As a child grows and matures, ART transforms from the administration of small amounts of liquid preparations to tablet formulations of coformulated ARV drugs. In this article, the authors review the evolution of ART throughout childhood from early infancy into adolescence.