Long‐Term Protease Inhibitor–Containing Therapy Results in Limited Improvement in T Cell Function but Not Restoration of Interleukin‐12 Production in Pediatric Patients with AIDS (original) (raw)
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Protease Inhibitor Therapy in HIV-Infected Children
AIDS Patient Care and STDs, 2000
We reviewed the short-term response to and safety of protease inhibitor (PI) therapy in HIVinfected children by performing a retrospective chart review of open-label PI containing combination therapy at two urban pediatric HIV centers. Seventy HIV-infected children received 101 PI containing antiretroviral therapy (ART) combinations. Main outcome measures were follow-up CD4 counts, viral loads, and patient or caregiver reported compliance. During follow-up, treatment with PI ART was associated with a mean maximal increase in CD4 1 lymphocyte count of 454 3 10 6 /L and a mean maximal decrease in viral load of 1.76 log units. Of the 32 patients who achieved undetectable viral loads, 28 (87.5%) remained undetectable through a mean follow-up of 8.9 months. Patients who reported good compliance achieved a higher rate of response (92.6%) than those who reported poor compliance (61.5%). Of 14 changes made to a second PI because of treatment failure, 11 (78.6%) resulted in a positive response to the second regimen. Nineteen of 101 courses of PI therapy resulted in significant side effects, including renal complications in 8 of 21 patients treated with indinavir. PI ART was associated with substantial short-term improvement in immunological and virological parameters in this heavily pretreated cohort, with 40% of patients maintaining an undetectable viral load after 9 months of therapy. Patients who failed one PI regimen usually responded to a second regimen. There was a significant rate of side effects from PI treatment.
Immunologic Research, 2008
Many HIV-infected children treated with protease inhibitors (PI) reconstitute immunity despite viral breakthrough predicting disease progression. We studied a unique cohort of PI treated children with advanced disease who demonstrated sustained CD4 T cell counts but median post therapy viral load rebounded to [4.0 log 10 copies/ml. Phylogenetic relationships between pre-and post-therapy viruses reveals significant bottlenecks for quasispecies with natural polymorphisms mapping outside of protease active site providing selective advantage for emergence. Among discordant subjects post-therapy viruses fell into two phenotypes; high viral loads (median [5.0 log 10 copies/ml) and Dedication to Dr. Robert A. Good: In many ways the HIV epidemic has defined modern human immunology. Early in the epidemic there was no readily available animal model to study pathogenesis. As a result physicians had to rely on clinical observations to understand disease progression and the factors leading to the development of AIDS. Imagine if Dr. Good's early work in defining the compartmentalization of adaptive immunity into T and B lymphocytes or his discovery of the important role of the thymus in T cell development had NOT occurred or happened years later? There would have been confusion and frustration in understanding, treating, and controlling this great new plague of mankind. Fortunately Dr. Good's focus on human immunology as well as his keen ability to make clinical observations and correlate them with functional immunity provided the basis of the future studies that defined the human immune system. Dr. Good and his collaborator's research facilitated the discovery of CD4 and CD8 T cells and laid the foundation for our understanding T cell homeostasis. Was it pure serendipity that the timeline of the most important human immune deficiency paralleled the great discoveries of human immunology spearheaded by Dr. Robert Good?
Journal of Infectious Diseases, 2000
The response of 40 immunologic parameters was studied for 147 clinically stable, protease inhibitor-naive, human immunodeficiency virus (HIV)-infected children aged 2-17 years when antiretroviral therapy was changed to either a dual nucleoside analogue regimen or a protease inhibitor-containing regimen. Immunologic response to therapy, as measured by lymphocyte subsets, 3-color flow cytometric measures, and lymphoproliferative assays, were investigated for changes in weeks 44 and 48. The most significant changes after baseline that were associated with the administration of a protease inhibitor-containing regimen were seen for percentages of CD8 + /CD38 + /HLA-DR + , CD8 + /CD95 + /CD28 Ϫ , and CD8. The percentages of CD8 + /CD38 + / HLA-DR + and CD8 + /CD95 + /CD28 Ϫ decreased from baseline medians of 33% and 46% to medians of 18% and 30% at week 44 ( for both). Median CD4 cell count increased P ! .0001
Scandinavian Journal of Immunology, 1999
The present study examines the influence of effective anti-retroviral treatment on immune function, evaluated by a broad array of immunological tests. We followed 12 individuals infected with human immunodeficiency virus (HIV) for 6 months after initiation of combination anti-retroviral treatment including a protease inhibitor. Unstimulated and pokeweed mitogen (PWM)-, interleukin (IL)-2-and phytohaemagglutinin (PHA)-stimulated lymphocyte proliferative responses increased during follow-up reaching average levels from 1.3-fold (PHA) to 3.7-fold (PWM) above baseline values. The total CD4 þ lymphocyte count increased mainly due to increases in numbers of CD4 þ CD28 þ and CD4 þ CD45RO þ cells, whereas increases in numbers of CD4 þ CD45RA þ cells contributed little to the increase in CD4 þ cell count. The total cytotoxic Tcell (CTL) killing of autologous B cells infected with HIV-encoding recombinant Vaccinia virus was increased after 3-6 months, whereas the specific HIV-directed CTL activity and the concentration and lytic activity of natural killer (NK) cells were unchanged during follow-up. These results demonstrate that the initiation of a treatment including an HIV protease inhibitor is followed by an increase in lymphocyte proliferation and lymphocyte-mediated cytotoxicity. However, unchanged levels of specific HIV CTL and NK cell activity warn us that not all measures of immune function may respond simultaneously to antiretroviral treatment.