T-Cell Activation Predict Antiretroviral Success in Salvage Therapy of HIV
T-Cell Activation Predict Antiretroviral Success in Salvage Therapy of HIV
Objective: Because effective antiretroviral therapy (ART) reduces immune activation, we hypothesize that early changes in immune activation are associated with subsequent virologic response to therapy.
Design: Observational cohort study.
Setting: Institutional HIV clinic.
Subjects: Thirty-four adult HIV patients with virologic failure on their current antiretroviral regimen.
Intervention: Change to salvage regimen selected by patient's physician.
Main Outcome Measures: Measures of immune activation at baseline and at 2, 4, 8, and 24 weeks after enrollment. Data were analyzed by proportional hazards (PH) models.
Results: PH models showed that reductions between baseline and week 2 in expression of CD38 (P = 0.02) or CD95 (P = 0.02) on CD4 T cells were associated with increased likelihood of achieving virologic suppression. Kaplan-Meier analysis demonstrated that patients who had reductions within the first 2 weeks of therapy in CD4 T-cell expression of CD38 (P = 0.003) or CD95 (P = 0.08) were more likely to achieve viral suppression than those who did not.
Conclusions: Reduced CD4 T-cell expression of CD38 and CD95 occurring within 2 weeks of salvage therapy is associated with subsequent viral suppression. Monitoring CD38 and CD95 may allow earlier assessment of the response to ART.
The management of HIV-infected patients is guided largely by 2 key measures: the amount of viral replication, which predicts the rate of disease progression, and the degree of immune system dysfunction as measured by absolute CD4 T-cell number. The continuing development of effective antiretroviral therapies (ARTs) has allowed pharmacologic suppression of HIV replication in many infected patients, often leading to quantitative and qualitative reconstitution of the immune system. Ongoing viral replication in the presence of incompletely suppressive drugs, when coupled with the labile genetic nature of HIV, may lead to resistance mutations, loss of virologic control, decreased CD4 T-cell number, and significant morbidity and mortality, however. Moreover, once resistance occurs, the likelihood of extended resuppression of viral replication with subsequent therapies is substantially lower. With the current practice of monitoring only viral replication and CD4 T-cell number, it may take several months to determine whether or not a new antiretroviral regimen is effective. Therefore, identifying markers that accurately predict at early time points whether there is likely to be eventual viral suppression, particularly in situations in which salvage drug regimens are required, would be of great clinical utility.
There has been considerable interest in evaluating markers of immune function to aid in the management of patients infected with HIV. Several immunologic markers have been proposed as predictors of disease outcome, including serum p24 antigen levels, serum tumor necrosis factor (TNF)-α and TNFγ levels, CD38 antigen intensity on CD8 T cells, and a variety of other T-cell activation markers (eg, CD95, human leukocyte antigen D-related [HLA-DR], CD28). Not all the previous studies evaluated patients who had previously received ART, however, and, often, only late time points (eg, ≥24 weeks after therapy) were analyzed. Although a study that analyzed earlier time points (beginning at 12 weeks) showed that the CD8CD38 T-cell count is a prognostic marker of therapeutic failure in HIV-infected children, no studies have evaluated the prognostic value of early changes in these immune markers in adult HIV-positive patients over time. Thus, it is unknown whether early changes in such markers in adult patients add prognostic information to the current standard clinical practice of monitoring CD4 T-cell counts and HIV viral load at intervals of every few months.
With the goal of identifying whether changes in immunologic markers that occur early after initiation of salvage therapy are associated with subsequent virologic response to therapy, a single-center cohort study was initiated. Multivariate flow cytometry was used to assess immune activation and T-cell subsets before and during salvage therapy to identify immunologic markers that predict within the first few weeks the subsequent restoration of virologic control.
Objective: Because effective antiretroviral therapy (ART) reduces immune activation, we hypothesize that early changes in immune activation are associated with subsequent virologic response to therapy.
Design: Observational cohort study.
Setting: Institutional HIV clinic.
Subjects: Thirty-four adult HIV patients with virologic failure on their current antiretroviral regimen.
Intervention: Change to salvage regimen selected by patient's physician.
Main Outcome Measures: Measures of immune activation at baseline and at 2, 4, 8, and 24 weeks after enrollment. Data were analyzed by proportional hazards (PH) models.
Results: PH models showed that reductions between baseline and week 2 in expression of CD38 (P = 0.02) or CD95 (P = 0.02) on CD4 T cells were associated with increased likelihood of achieving virologic suppression. Kaplan-Meier analysis demonstrated that patients who had reductions within the first 2 weeks of therapy in CD4 T-cell expression of CD38 (P = 0.003) or CD95 (P = 0.08) were more likely to achieve viral suppression than those who did not.
Conclusions: Reduced CD4 T-cell expression of CD38 and CD95 occurring within 2 weeks of salvage therapy is associated with subsequent viral suppression. Monitoring CD38 and CD95 may allow earlier assessment of the response to ART.
The management of HIV-infected patients is guided largely by 2 key measures: the amount of viral replication, which predicts the rate of disease progression, and the degree of immune system dysfunction as measured by absolute CD4 T-cell number. The continuing development of effective antiretroviral therapies (ARTs) has allowed pharmacologic suppression of HIV replication in many infected patients, often leading to quantitative and qualitative reconstitution of the immune system. Ongoing viral replication in the presence of incompletely suppressive drugs, when coupled with the labile genetic nature of HIV, may lead to resistance mutations, loss of virologic control, decreased CD4 T-cell number, and significant morbidity and mortality, however. Moreover, once resistance occurs, the likelihood of extended resuppression of viral replication with subsequent therapies is substantially lower. With the current practice of monitoring only viral replication and CD4 T-cell number, it may take several months to determine whether or not a new antiretroviral regimen is effective. Therefore, identifying markers that accurately predict at early time points whether there is likely to be eventual viral suppression, particularly in situations in which salvage drug regimens are required, would be of great clinical utility.
There has been considerable interest in evaluating markers of immune function to aid in the management of patients infected with HIV. Several immunologic markers have been proposed as predictors of disease outcome, including serum p24 antigen levels, serum tumor necrosis factor (TNF)-α and TNFγ levels, CD38 antigen intensity on CD8 T cells, and a variety of other T-cell activation markers (eg, CD95, human leukocyte antigen D-related [HLA-DR], CD28). Not all the previous studies evaluated patients who had previously received ART, however, and, often, only late time points (eg, ≥24 weeks after therapy) were analyzed. Although a study that analyzed earlier time points (beginning at 12 weeks) showed that the CD8CD38 T-cell count is a prognostic marker of therapeutic failure in HIV-infected children, no studies have evaluated the prognostic value of early changes in these immune markers in adult HIV-positive patients over time. Thus, it is unknown whether early changes in such markers in adult patients add prognostic information to the current standard clinical practice of monitoring CD4 T-cell counts and HIV viral load at intervals of every few months.
With the goal of identifying whether changes in immunologic markers that occur early after initiation of salvage therapy are associated with subsequent virologic response to therapy, a single-center cohort study was initiated. Multivariate flow cytometry was used to assess immune activation and T-cell subsets before and during salvage therapy to identify immunologic markers that predict within the first few weeks the subsequent restoration of virologic control.
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