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Joint evolution of CD4 and viral load trajectories over 2 years in an early-treated pediatric African cohort

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BACKGROUND: In response to antiretroviral therapy (ART), some patients experience a discordant response, characterized either by a high CD4+ cell count despite persistent viremia or by viral suppression with low CD4+ cell count. Little is known about the meaning of discordant responses in children reported to be 10-20%. In this study, we analyze virologic and immunologic phenotypes, including a discordant response based on trajectories instead of arbitrary thresholds.
METHODS: This study was done within the EARTH Cohort, a prospective cohort enrolling perinatally HIV infected infants diagnosed in the first 3 months of life and treated after diagnosis, in Mozambique and South Africa. During 2-years of follow-up, the trajectories of CD4 and VL were calculated using KmL3D R package that implements k-means dedicated to clustering joint-trajectories. Optimum number of clusters was based on the Calinski-Harabatz criterium. Comparisons between clusters were assessed by the Kruskal-Wallis and Fisher test.
RESULTS: A total of 59 patients with at least 5 measurements of CD4 and VL were included in this study. Four robust clusters were selected. The participants in Cluster A (23/59 (39.0%)) presented virological failure and poor %CD4 reconstitution after treatment. They were treated later, and they had high VL and low %CD4 at ART initiation. Cluster B (19/59 (32.2%)) had participants who achieved viral suppression and had consistently high %CD4. A total of 17/59 (28.8%) patients presented discordant responses. Patients included in Cluster C (16/59 (27.1%)) presented a viral failure and high good CD4 reconstitution, and patients included in Cluster D (1/59 (1.7%)) also presented discordant response, in this case, viral suppression and poor CD4 reconstitution. Despite acceptable CD4 levels, patients with discordant responses presented higher rates of clinical progression (37.5%) (WHO stage III-IV) than those with viral suppression and good CD4 response (1/19 (5.3%)), p=0.015. Patients with discordant responses were more frequently treated with ART regimens including protease inhibitors (p=0.047).
CONCLUSIONS: A higher rate of discordant responses was present in this study (28.8%) compared to previous reports. The characterization of immunologic and virologic status of the patients could help in the design of personalized therapeutic interventions and in identifying patients for trials.