Causes of death in pediatric patients vertically infected by the human immunodeficiency virus type 1 in Madrid, Spain, from 1982 to mid-2009.

BACKGROUND: Effective therapies have increased life expectancy of human immunodeficiency virus (HIV)-infected pediatric patients. We investigated the underlying causes of death, mortality, and acquired immune deficiency syndrome (AIDS) rates in HIV-infected pediatric patients in Madrid, Spain. METHODS: We studied a multicenter cohort of 478 HIV-infected pediatric patients in Madrid. Mortality and AIDS incidence rates, causes of death, CD4 T-cell, and HIV RNA were analyzed during calendar periods (CPs): pre-HAART (highly active antiretroviral therapy) (CP1: 1982-1996) and post-HAART era (CP2: 1997-2009). RESULTS: During 5690 person-years of follow-up 157 (32.8%) deaths occurred. Median age at death increased (CP1: 3.2 years [1.0-6.3] vs. CP2: 7.7 years [3.1-11.4]; P < 0.01). Mortality and AIDS rates decreased 10.6-fold (95% confidence intervals [CI]: 6.9-16.7) and 6.9-fold (95% CI: 5.0-9.6), respectively, between CPs. Nevertheless, mortality was 10.4-fold (95% CI: 5.8-18.8; P < 0.001) higher than in age-similar general population in late-CP2. In all, 169 causes of death were reported. Multiple causes were reported in 16 of 151 (10.6%) patients. In 81.1% (137/169), the causes were AIDS-defining, 11.8% (20/169) HIV-related, and 7.1% (12/169) non-HIV-related. Infections were the leading causes (60.8%, 101/166); from 1999 to 2007 the risk of death from infections was 115.9 times (95% CI: 42.0-265.8; P < 0.001) higher than in the age-similar general population. Comorbidity was reported in 66.9% (101/151) of patients. Median HIV-1 RNA at death decreased (CP1: 5.9 [5.0-6.3]; CP2: 5.3 [4.2-5.8]; P < 0.01). CONCLUSIONS: Despite decline in mortality and AIDS rates, it is important to monitor all causes of death as prolonged survival might allow underlying comorbidity to become more clinically relevant.

Long-term response to highly active antiretroviral therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children.

BACKGROUND: Immune recovery after prolonged highly active antiretroviral therapy (HAART) with lopinavir/ritonavir has been reported in adults but not in children. Our study aimed at evaluating the long-term use of lopinavir/ritonavir among children in a clinical setting. METHODS: We carried out a retrospective study on 69 protease inhibitor (PI)-experienced vertically HIV-infected children on HAART containing lopinavir/ritonavir. We analysed the changes in percentage CD4+ cell count (%CD4+) and viral load (VL) and identified prognostic factors to achieve CD4+ >25% and undetectable VL (uVL) ( 100,000 copies/mL. We found that %CD4+ at baseline had a strong positive association with achieving CD4+ >25% at 6, 12, 18, 24, 36 and 48 months of follow-up. We also found that length of PI use had a negative association with reaching CD4+ >25% at 24 and 48 months and achieving uVL at 12 and 24 months. VL at baseline had a negative association with achieving uVL at 18 and 24 months. CONCLUSIONS: Our study demonstrates ongoing immune recovery among children on HAART with lopinavir/ritonavir after 4 years of follow-up. Lopinavir/ritonavir, when given as part of a salvage regimen, is safe and well tolerated in HIV-infected children.

Impact of highly active antiretroviral therapy on CD4+ T cells and viral load of children with AIDS: a population-based study.

In this study, we sought to characterize the changes over time at the population level on CD4(+) T cells and plasma viral load (VL) levels of HIV-1-infected children with or without AIDS. We carried out a retrospective study in 114 HIV-infected children during the calendar period that a highly active antiretroviral therapy (HAART) protocol was used. The HAART protocol consisted of three drugs: nucleoside analogue HIV-1 reverse transcriptase inhibitors, and/or HIV protease inhibitors, and/or nonnucleoside analogue HIV-1 reverse transcriptase inhibitors. The mean of CD4(+) T cells percentage and log(10) VL per calendar year were stratified by AIDS diagnostic. As new HAART strategies become available, an increase of CD4(+) T cells and a decrease of VL were observed over time, in children with and without AIDS. In 2001, children with AIDS reached values of CD4(+) T cells and VL similar to children without AIDS. In conclusion, our study shows that the generalized use of HAART has permitted improvement in immunological and virological status of HIV-infected children without AIDS, and more importantly in children with AIDS.

CD38 expression in CD8+ T cells predicts virological failure in HIV type 1-infected children receiving antiretroviral therapy.

An observational study of children vertically infected with human immunodeficiency virus type 1 (HIV-1) was performed to determine the role of CD38 expression in CD8(+) T cells as prognostic marker of virological failure in children receiving HAART. We studied 42 children who were receiving antiretroviral therapy and who had an undetectable virus load (uVL), and we found a negative correlation between CD38 expression in CD8(+) T cells and the duration of uVL. We selected 17 HIV-1-infected children with CD38 values close to the baseline level (i.e., the first uVL achieved), and we distributed the children into 2 groups on the basis of median CD38 value in CD8(+) T cells. Children with CD38 values in CD8(+) T cells that were higher than the median had a higher incidence and relative risk of virological failure than did those with values lower than the median. In conclusion, we demonstrate for the first time that CD8(+)CD38(+) T cell count is a good prognostic marker of therapeutic failure in HIV-1-infected children.

Papel de las citocinas y las quimiocinas en la no progresión de la infección por VIH-1 en niños infectados verticalmente / Role of cytokines and chemokines in the non progression of the HIV-1 infection in vertically infected children

Fundamento: Estudiar la producción de citocinas en niños infectados verticalmente por VIH-1 con una duración de la infección mayor de 7 años y diferente velocidad de progresión. Pacientes y métodos: Estudiamos a 32 niños con VIH-1, divididos en: a) 8 niños NA (> 7 años, asintomáticos o con síntomas leves, sin tratamiento antirretroviral y linfocitos TCD4+ > 25 por ciento); b) 10 niños NE2 (> 6 años, sintomáticos, con tratamiento antirretroviral y linfocitos TCD4+ > 25 por ciento); c) 14 niños NE2-3 (> 6 años, sintomáticos, con tratamiento antirretroviral y linfocitos TCD4+ < 25 por ciento), y d) 16 niños controles, sin infección por el VIH (grupo C). Las células mononucleares de sangre periférica (CMSP) se cultivaron, y se cuantificó la producción de IL-2, IL-5, IL-10, TNF-*, IFN-* y RANTES en el sobrenadante. Resultados: Las CMSP sin estimular de los niños con infección por VIH-1 produjeron más TNF-* y menos IL-2 que los controles. La producción de IFN-* fue menor en los grupos NE1 y NE2-3 que en el control. El grupo NA produjo más IFN-* que el NE2-3. En las CMSP estimuladas con fitohemaglutinina (PHA), la producción de TNF-* fue mayor en los grupo NA y NE1 que en el control. La IL-2 de los grupos NA y NE1 fue similar al control, pero el grupo NE2-3 produjo menos IL-2 que el control y NE1. La producción de IFN-* y RANTES fue significativamente mayor en NA que en el control. Los grupos NE1 y NE2-3 produjeron menos IL-5 que el control y NA. El grupo NE2-3 produjo menos IL-10 que el control. El cociente IFN-*/IL-5 e IFN-*/IL-10 fue mayor en NA que en el control y NE1. Conclusiones: En niños sin progresión se conserva la funcionalidad inmunológica y la respuesta de los linfocitos Th1 se halla incrementada, mientras que en los niños con progresión tratados se observa una disminución de la producción de citocinas por los linfocitos Th2. Nuestros datos indican claramente que la disminución de IL-2 es un marcador temprano de evolución de la infección por el VIH y que valores elevados de RANTES no son indicativos de falta de progresión. (AU)