Individual Differences in CD4/CD8 T-Cell Ratio Trajectories and Associated Risk Profiles Modeled From Acute HIV Infection

Robert Paul, Kyu Cho, Jacob Bolzenius, Carlo Sacdalan, Lishomwa C Ndhlovu, Lydie Trautmann, Shelly Krebs, Somporn Tipsuk, Trevor A Crowell, Duanghathai Suttichom, Donn J Colby, Thomas A Premeaux, Nittaya Phanuphak, Phillip Chan, Eugène Kroon, Sandhya Vasan, Denise Hsu, Adam Carrico, Victor Valcour, Jintanat Ananworanich, Merlin L Robb, Julie A Ake, Somchai Sriplienchan, Serena Spudich, RV254/SEARCH 010 Study Team, Robert Paul, Kyu Cho, Jacob Bolzenius, Carlo Sacdalan, Lishomwa C Ndhlovu, Lydie Trautmann, Shelly Krebs, Somporn Tipsuk, Trevor A Crowell, Duanghathai Suttichom, Donn J Colby, Thomas A Premeaux, Nittaya Phanuphak, Phillip Chan, Eugène Kroon, Sandhya Vasan, Denise Hsu, Adam Carrico, Victor Valcour, Jintanat Ananworanich, Merlin L Robb, Julie A Ake, Somchai Sriplienchan, Serena Spudich, RV254/SEARCH 010 Study Team

Abstract

Objective: We examined individual differences in CD4/CD8 T-cell ratio trajectories and associated risk profiles from acute HIV infection (AHI) through 144 weeks of antiretroviral therapy (ART) using a data-driven approach.

Methods: A total of 483 AHI participants began ART during Fiebig I-V and completed follow-up evaluations for 144 weeks. CD4+, CD8+, and CD4/CD8 T-cell ratio trajectories were defined followed by analyses to identify associated risk variables.

Results: Participants had a median viral load (VL) of 5.88 copies/ml and CD4/CD8 T-cell ratio of 0.71 at enrollment. After 144 weeks of ART, the median CD4/CD8 T-cell ratio was 1.3. Longitudinal models revealed five CD4/CD8 T-cell ratio subgroups: group 1 (3%) exhibited a ratio >1.0 at all visits; groups 2 (18%) and 3 (29%) exhibited inversion at enrollment, with normalization 4 and 12 weeks after ART, respectively; and groups 4 (31%) and 5 (18%) experienced CD4/CD8 T-cell ratio inversion due to slow CD4+ T-cell recovery (group 4) or high CD8+ T-cell count (group 5). Persistent inversion corresponded to ART onset after Fiebig II, higher VL, soluble CD27 and TIM-3, and lower eosinophil count. Individuals with slow CD4+ T-cell recovery exhibited higher VL, lower white blood cell count, lower basophil percent, and treatment with standard ART, as well as worse mental health and cognition, compared with individuals with high CD8+ T-cell count.

Conclusions: Early HIV disease dynamics predict unfavorable CD4/CD8 T-cell ratio outcomes after ART. CD4+ and CD8+ T-cell trajectories contribute to inversion risk and correspond to specific viral, immune, and psychological profiles during AHI. Adjunctive strategies to achieve immune normalization merit consideration.

Trial registration: ClinicalTrials.gov NCT00796146.

Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.

Figures

FIGURE 1
FIGURE 1
CD4+, CD8+, and CD4/CD8 T-cell ratio trajectories defined by the group based multitrajectory analysis. CD4+ T-cell (top row), CD8+ T-cell (middle row), and CD4/CD8 T-cell ratio (bottom row) trajectories. Trajectory group 1 includes individuals with CD4/CD8 T-cell ratio ≥1.0 at enrollment and each follow-up visit. Trajectory group 2 includes individuals who achieved normalization by week 4 after ART onset. Trajectory group 3 represents individuals who achieved normalization by week 12. Trajectory group 4 represents individuals with persistent inversion despite 144 weeks of ART due to slow CD4+ T-cell recovery after ART. Trajectory group 5 represents individuals with persistent inversion due to high CD8+ T-cell count. ART = antiretroviral therapy.
FIGURE 2
FIGURE 2
Machine learning classification of slow CD4+ T-cell recovery versus high CD8+ T-cell count. Variables at baseline that collectively classified individuals into trajectory group 4 (slow CD4+ T-cell recovery) versus trajectory group 5 (consistently high CD8+ T-cell count). Variables are listed in rank order of relevance to classification accuracy: a) total white blood cell count, b) QOL item 15 (“How well are you able to get around?”), c) VL (absolute), d) Color Trails 1 performance (psychomotor speed), e) VL (log10 transformed), f) QOL item 6 (“To what extent do you feel your life to be meaningful?”), g) QOL item 13 (“How available to you is the information that you need in your day-to-day life?”), h) ART randomization to a boosted regimen versus standard ART, i) basophil percent, and j) response to PHQ-9 item 10 (“If you checked off any problems, how difficult have these problems made it for you to do your work, take care of things at home, or get along with other people?”). Unfavorable values predicted classification in trajectory group 4. Randomization to intensified ART predicted classification in trajectory group 5. GBM = gradient-boosted multivariate regression; HAART = highly active antiretroviral therapy; QOL = quality of life; PHQ-9 = Patient Health Questionnaire-9; VL = viral load.

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