Incomplete Peripheral CD4⁺Cell Count Restoration in HIV‐Infected Patients Receiving Long‐Term Antiretroviral Treatment

Abstract

Background Although antiretroviral therapy has the ability to fully restore a normal CD4+ cell count (>500 cells/mm3) in most patients, it is not yet clear whether all patients can achieve normalization of their CD4+ cell count, in part because no study has followed up patients for >7 years. Methods Three hundred sixty-six patients from 5 clinical cohorts who maintained a plasma human immunodeficiency virus (HIV) RNA level ≤1000 copies/mL for at least 4 years after initiation of antiretroviral therapy were included. Changes in CD4+ cell count were evaluated using mixed-effects modeling, spline-smoothing regression, and Kaplan-Meier techniques. Results The majority (83%) of the patients were men. The median CD4+ cell count at the time of therapy initiation was 201 cells/mm3 (interquartile range, 72−344 cells/mm3), and the median age was 47 years. The median follow-up period was 7.5 years (interquartile range, 5.5−9.7 years). CD4+ cell counts continued to increase throughout the follow-up period, albeit slowly after year 4. Although almost all patients (95%) who started therapy with a CD4+ cell count ≥300 cells/mm3 were able to attain a CD4+ cell count ≥500 cells/mm3, 44% of patients who started therapy with a CD4+ cell count <100 cells/mm3 and 25% of patients who started therapy with a CD4+ cell count of 100−200 cells/mm3 were unable to achieve a CD4+ cell count >500 cells/mm3 over a mean duration of follow-up of 7.5 years; many did not reach this threshold by year 10. Twenty-four percent of individuals with a CD4+ cell count <500 cells/mm3 at year 4 had evidence of a CD4+ cell count plateau after year 4. The frequency of detectable viremia (“blips”) after year 4 was not associated with the magnitude of the CD4+ cell count change. Conclusions A substantial proportion of patients who delay therapy until their CD4+ cell count decreases to <200 cells/mm3 do not achieve a normal CD4+ cell count, even after a decade of otherwise effective antiretroviral therapy. Although the majority of patients have evidence of slow increases in their CD4+ cell count over time, many do not. These individuals may have an elevated risk of non–AIDS-related morbidity and mortality.

The role of SNPs in the α-chain of the IL-7R gene in CD4+ T-cell recovery in HIV-infected African patients receiving suppressive cART

“…1,59 We found that the identical clinical parameters were associated with increased rate of CD4 T-cell recovery by using both approaches and were consistent with other observational studies of CD4 T-cell recovery after cART. 2,16 It is important to note however, that this study was designed to replicate our previous study of Caucasians 22 where we had previously used a survival analysis approach.…”

“…[1][2][3] These patients remain at increased risk of non-AIDS-related illnesses and mortality despite years of suppressive cART. [4][5][6] Clinical or genetic factors that may predict impaired CD4 T-cell recovery could potentially be used to identify patients who would benefit from earlier initiation of cART.…”

“…12,13 Previous studies have found that impaired IL-7 responsiveness is significantly associated with poor CD4 T-cell recovery following cART. 14,15 Various clinical factors have been associated with impaired CD4 T-cell reconstitution following cART, including lower CD4 T-cell counts at initiation of cART, [16][17][18][19] being older at cART initiation 1,17,19,20 and higher levels of immune activation both before and while on cART as measured by T-cell activation markers (such as human leukocyte antigen (HLA)-DR þ CD38 þ expression). [21][22][23][24] Multiple host genetic factors have also been found to influence CD4 T-cell recovery.…”

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

“…500 mL) after a mean time of 7.5 y on antiretroviral therapy (ART) (1). Persistent depletion of CD4 + T cells in lymphoid tissue, such as gut-associated lymphoid tissue, is even more pronounced than in blood (2).…”

HIV-1 Pathogenesis: The Virus

“…The extent of the damage is related to the length of time of infection (or more appropriately to the nadir of CD4 þ Tcell count). This damage is seen by an inability to completely replace the CD4 þ T-cell compartment after therapy in initiated (Kelley et al 2009), which may be due in part to depletion of the host capacity to generate CD4 þ T cells over time, or to damage of the architecture of the lymphoid tissue that results in reduced capacity to support CD4 þ T-cell function (Lackner et al 2011). …”