Two-Year Clinical and Immune Outcomes in Human Immunodeficiency Virus–Infected Children Who Reconstitute CD4 T Cells Without Control of Viral Replication After Combination Antiretroviral Therapy

Ghaffari, Guity; Passalacqua, Dominick J.; Caicedo, Jennifer L.; Goodenow, Maureen M.; Sleasman, John W.

doi:10.1542/peds.2004-0274

Cited by 38 publications

(48 citation statements)

References 36 publications

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“…Previous studies have concluded that CD4 monitoring is more appropriate than virologic monitoring because a decreasing CD4 count is a better predictor of disease progression. 7 Early detection of treatment failure is important to limit the selection of resistance mutations, although it remains unclear at which level of detectable viral load patients should be switched. 20 All but 1 patient with a viral load of Ͼ1000 copies per mL had developed Ն1 resistance mutation indicating failure to the first-line HAART regimen.…”

Section: Discussionmentioning

confidence: 99%

“…1 Of the 39.5 million people who were estimated to be living with HIV/AIDS in 2006, 2.3 million were children who were younger than 15; more than half a million children died of HIV/AIDS that year. 2 In the West, good outcomes are achieved for children who are on highly active antiretroviral therapy (HAART), [3][4][5][6][7] and studies indicate that similar outcomes can be achieved in resource-limited settings. [8][9][10][11] However, documented experience of treating large numbers of children remains limited.…”

Section: Methods Between June 2003 and March 2005mentioning

confidence: 99%

See 1 more Smart Citation

Effectiveness of Highly Active Antiretroviral Therapy in HIV-Positive Children: Evaluation at 12 Months in a Routine Program in Cambodia

Janssens¹,

Raleigh²,

Soeung

et al. 2007

Pediatrics

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OBJECTIVE. Increasing access to highly active antiretroviral therapy to reach all those in need in developing countries (scale up) is slowly expanding to HIV-positive children, but documented experience remains limited. We aimed to describe the clinical, immunologic, and virologic outcomes of pediatric patients with >12 months of highly active antiretroviral therapy in 2 routine programs in Cambodia. METHODS. Between June 2003 and March 2005, 212 children who were younger than 13 years started highly active antiretroviral therapy. Most patients started a standard first-line regimen of lamivudine, stavudine, and nevirapine, using split adult fixed-dosage combinations. CD4 percentage and body weight were monitored routinely. A cross-sectional virologic analysis was conducted in January 2006; genotype resistance testing was performed for patients with a detectable viral load. RESULTS. Mean age of the subjects was 6 years. Median CD4 percentage at baseline was 6. Survival was 92% at 12 months and 91% at 24 months; 13 patients died, and 4 were lost to follow-up. A total of 81% of all patients had an undetectable viral load. Among the patients with a detectable viral load, most mutations were associated with resistance to lamivudine and non–nucleoside reverse-transcriptase inhibitor drugs. Five patients had developed extensive antiretroviral resistance. Being an orphan was found to be a predictor of virologic failure. CONCLUSIONS. This study provides additional evidence of the effectiveness of integrating HIV/AIDS care with highly active antiretroviral therapy for children in a routine setting, with good virologic suppression and immunologic recovery achieved by using split adult fixed-dosage combinations. Viral load monitoring and HIV genotyping are valuable tools for the clinical follow-up of the patients. Orphans should receive careful follow-up and extra support.

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Section: Discussionmentioning

confidence: 99%

Section: Methods Between June 2003 and March 2005mentioning

confidence: 99%

Effectiveness of Highly Active Antiretroviral Therapy in HIV-Positive Children: Evaluation at 12 Months in a Routine Program in Cambodia

Janssens¹,

Raleigh²,

Soeung

et al. 2007

Pediatrics

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“…In HAART-treated children, immune repopulation may occur despite persistent viraemia [15,16,[19][20][21][22]. To add to the scarce information available on immune reconstitution in HIV-1-infected children, we investigated peripheral immune repopulation in children with and without a virological response to therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, some children show a discordant response to HAART characterized by a significant increase in CD4 + T cell counts, despite persistent detectable viraemia [15,16,[19][20][21][22]. Although the mechanisms of this discordant response to HAART have not been elucidated fully, it has been suggested that thymic output [15,16,19,23] and an impaired replicative capacity of drug-resistant viruses [20,24,25] might be involved.…”

Section: Introductionmentioning

confidence: 99%

Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy

Anselmi

Vendrame

Rampon

et al. 2007

Clinical and Experimental Immunology

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“…Differences in CDR3 length diversity within the CD4 or the CD8 CD45RA or CD45RO subset enable assessments of disruptions of the TCR repertoire and the detection of oligoclonal expansion that would have been missed if the analysis were limited to unfractionated T cells (25,26). While optimal control of viral replication by antiretroviral therapy (ART) corrects many T-cell abnormalities and slows the progression to AIDS, it is not clear if therapy completely restores the TCR repertoire or fully diminishes T-cell activation (7,14,27,51). In the present study, we examined the relationship of TCR diversity, thymic output, and the expression of T-cell activation markers within the CD45RA and CD45RO subpopulations of CD4 and CD8 T cells before and after the initiation of ART to determine the extent to which the control of viral replication restores the TCR repertoire.…”

mentioning

confidence: 99%

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

Yin¹,

Kou²,

Rodriguez

et al. 2009

Clin Vaccine Immunol

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Human immunodeficiency virus (HIV) type 1 infection perturbs the T-cell receptor (TCR) V␤ repertoire.The TCR CDR3 length diversity of individual V␤ families was examined within CD45RA and CD45RO CD4 T cells to assess the impact of the virus on clonality throughout CD4 T-cell activation and differentiation. A cross-sectional and longitudinal cohort study of 13 HIV-infected and 8 age-matched healthy children and adolescents examined the V␤ CDR3 length profiles within CD4 T-cell subsets by the use of spectratyping. HIV-infected subjects demonstrated higher numbers of perturbations in CD4 CD45RA T cells (5.8 ؎ 4.9 V␤ families) than healthy individuals (1.6 ؎ 1.8 V␤ families) (P ‫؍‬ 0.04). Surprisingly, CD4 CD45RO central memory T cells from infected subjects showed no increased perturbations compared to the perturbations for the same cells from healthy subjects (2.9 ؎ 3.1 and 1.1 ؎ 1.8 V␤ families, respectively; P ‫؍‬ 0.11). CD4 CD45RA TCR perturbations were higher among infected subjects with >25% CD4 cells than healthy subjects (mean number of perturbed V␤ families, 6.6 ؎ 5.4; P ‫؍‬ 0.04). No correlations between perturbations in CD4 subsets and pretherapy age or viral load were evident. In contrast to CD8 T cells, HIV induces TCR disruptions within CD45RA but not CD45RO CD4 T cells. Therapy-induced viral suppression resulted in increases in thymic output and the normalization of the diversity of TCR within CD45RA CD4 T cells after 2 months of treatment. Perturbations occur prior to CD4 T-cell attrition and normalize with effective antiretroviral therapy. The impact of HIV on the diversity of TCR within naïve, central memory, and effector memory CD4 T cells is distinctly different from that in CD8 T cells.Human immunodeficiency virus type 1 (HIV-1) infection alters T-cell homeostasis by both impairing thymic output and inducing chronic T-cell activation. These disruptions are manifest by the increased level of expression of T-cell activation markers and decreased numbers of naïve T cells from the thymus (10,12,51). Oligoclonal T-cell expansion results in perturbations of the T-cell receptor (TCR) V␤ repertoire within both CD4 and CD8 T cells, with CD8 T cells being affected to a greater extent than CD4 T cells (7,12,16,29,50). Many of these abnormalities occur prior to CD4 T-cell attrition and are not fully reconstituted when viral replication is controlled by antiretroviral therapy (6, 17, 30). Multiple mechanisms have been postulated to contribute to this processes of aberrant T-cell activation and clonal expansion, including microbial translocation across the gastrointestinal tract as a result of virus-induced intestinal fibrosis (4,5,40) and the loss of immune regulation due to chronic HIV-induced antigenemia (8,22).CD4 and CD8 T cells are heterogeneous populations that differ functionally and in their expression of activation and differentiation markers, forming the basis of their classification as naïve, central memory (CM), or effector memory (EM) T cells (42). Isoforms of CD45 (CD45RA and CD45RO) are frequ...

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Two-Year Clinical and Immune Outcomes in Human Immunodeficiency Virus–Infected Children Who Reconstitute CD4 T Cells Without Control of Viral Replication After Combination Antiretroviral Therapy

Cited by 38 publications

References 36 publications

Effectiveness of Highly Active Antiretroviral Therapy in HIV-Positive Children: Evaluation at 12 Months in a Routine Program in Cambodia

Effectiveness of Highly Active Antiretroviral Therapy in HIV-Positive Children: Evaluation at 12 Months in a Routine Program in Cambodia

Immune reconstitution in human immunodeficiency virus type 1-infected children with different virological responses to anti-retroviral therapy

Antiretroviral Therapy Restores Diversity in the T-Cell Receptor Vβ Repertoire of CD4 T-Cell Subpopulations among Human Immunodeficiency Virus Type 1-Infected Children and Adolescents

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