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Accelerated aging in perinatally HIV-infected children: clinical manifestations and pathogenetic mechanisms
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CONCLUSIONS
After the introduction of ART, HIV infection became a chronic disease, but HIV-infected children have not yet the same life expectancy of healthy children. The infection behaves differently in children and adults, with important clinical and immunological differences. ART and HIV infection coexist in children from birth, moving up immunosenescence and aging processes; these are more pronounced in children with detectable viremia, focusing attention on the need for early and long-standing control of HIV replication. The pathogenic mechanisms of immunosenescence are various, not completely identified and partly different from those described in adults. Senescent phenotype of T cells makes children more susceptible to infections and less responsive to vaccination. HIV-infected children and adolescents should be carefully monitored for the prompt detection and early treatment of noninfectious disorders related to premature aging. Notably, lipid and bone metabolism, cancers, cardiovascular, renal, and neurological systems must be carefully monitored adopting screening programs and preventive measures in high risk populations, such as children with detectable viremia or with CD4/CD8 ratio inversion, mainly due to increased levels of senescent and/or activated CD8+ lymphocytes. The datum that no premature aging effect has been described regarding several organ systems may depend on the fact that no investigation has been executed to date and further studies are needed before excluding premature senescence of these organs. Finally, further studies regarding the mechanisms involved in premature aging are needed to search for potential targets of treatment.
premature aging in children
despite ART, the lifespan of HIV-infected individuals in Western countries is shortened by an average of 10 years [2], and accelerate aging processes and occurrence of precocious diseases have been reported in comparison to age-matched HIV-uninfected controls
Accumulating data suggest that aging process does not spare HIV-infected children, as well as adults.
Chronic immune activation because of persistence of circulating virions may play a role in the senescence pathway.
An important feature of aging and most of age-related diseases is chronic inflammation.
Results from several studies suggest that peripheral blood lymphocytes of perinatally HIV-infected children have typical features of an aging immune system.
NRTIs, such as zidovudine and abacavir, may inhibit TERT and consequently telomerase activity, leading to premature telomeres shortening [82-84]. This inhibition has been shown in in vitro systems [83,84] but the role of NRTIs in telomerase activity and subsequent telomere length in HIV-infected patients is an update question.
HIV infection is now considered a chronic disease which persists for many decades. However, it has been estimated that HIV-infected children display mortality rates 30 times higher than uninfected children due to chronic diseases, such as metabolic, cardiovascular, kidney and neurological disorders, and cancers [7-11]. These "non-AIDS related pathologies" represent a group of conditions possibly associated with HIV-mediated aging; the ongoing inflammatory immune process, that may persist despite ART, may also drive the premature cellular aging. The whole picture is complex and probably due to the interaction of multiple biologic and pharmacologic mechanisms (Table 1).
Renal function of HIV-infected children may be impaired not only due to the classic HIV-associated nephropathy (HIVAN), commonly reported in the pre-ART era, but also for the development of hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, acute kidney injury, renal nephrotoxicity syndromes associated with some specific antiretroviral drugs (i.e. tenofovir), and for the ongoing inflammatory process. Overall, these conditions lead to a premature loss of renal function [17-19].
Before the introduction of ART, HIV-infected children were often affected by HIV encephalopathy characterized by impaired brain growth, motor deficits and developmental delay [26]. After the introduction of ART, HIV encephalopathy has declined from 30%-50% to <2%, but other neuropsychological disorders have been reported at higher rates than in HIV-uninfected sex and age matched-controls with same ethnicity and socioeconomic status [27]. In addition, lower total intelligence quotient, language impairment, poorer working memory, gross and fine motor functioning and visual-motor impairment have been extensively reported in ART-treated HIV-infected children, more frequently than in healthy controls [27-30].
Children with HIV infection can develop precocious bone abnormalities with an increased risk of osteoporosis and fractures [36]. The risk of bone disorder is greater in children than in adults, because bone mass increases during childhood, accelerating during adolescence [37,38]. The cause is multifactorial and not fully clear, but many demographic, genetic, hormonal, nutritional factors, HIV levels and drugs are involved. Long-term ART, especially including tenofovir, disoproxil, and fumarate, is associated with greater bone loss [36,37].
After the introduction of ART, cardiovascular risk and incidence of related cardiovascular complications (i.e. cardiomyopathy) decreased significantly. However, asymptomatic structural abnormalities in HIV-infected children persist during ART and they may be related to subsequent clinically evident diseases in adult life [46].
HIV infected children may show changes in lipid and glucose metabolism including lipodystrophy, dyslipidemia, and glucose intolerance that predispose to early cardiovascular disease. The main cause of these alterations seems to be the antiretroviral therapy, but a role of HIV infection itself cannot be excluded because lipodystrophy and dyslipidemia has been described in HIV-infected children ART-naïve [53].
HIV-infected children display an increased cancer risk. Since ART introduction decreased rates of the three AIDS defining malignancies (ADM), i.e. Kaposi sarcoma, non-Hodgkin lymphoma (NHL) and cervical cancer, have been reported in children [54]. However, the incidence of several other "non-ADM" is increasing [10].
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