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/mm(3)) 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/mm(3) (interquartile range, 72-344 cells/mm(3)), 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/mm(3) were able to attain a CD4(+) cell count 500 cells/mm(3), 44% of patients who started therapy with a CD4(+) cell count <100 cells/mm(3) and 25% of patients who started therapy with a CD4(+) cell count of 100-200 cells/mm(3) were unable to achieve a CD4(+) cell count >500 cells/mm(3) 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/mm(3) 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/mm(3) 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.

Figure 1

Peripheral CD4⁺ cell counts in patients who had maintained viral suppression for 10 continuous years. Only those who had a pretherapy CD4⁺ cell count <200 cells/mm³ are shown (n = 48). A significant subset of individuals appeared to have their CD4⁺ cell counts plateau below normal levels (defined here as 500 cells/mm³).

Figure 2

The time from initiation of HAART to achievement of a CD4⁺ cell count >500 cells/mm³, estimated using Kaplan-Meier techniques. The cohort was selected on the basis of having achieved and maintained a viral load <1000 copies/mL for at least 4 years. Patients were stratified on the basis of their CD4⁺ cell counts at year 4 (74 had a CD4⁺ cell count <350 cells/mm³, 76 had a CD4⁺ cell count of 350−500 cells/mm³, and 216 had a CD4⁺ cell count >500 cells/mm³). The time from initiation of HAART to achievement of a CD4⁺ cell count >500 cells/mm³ was significantly different among the strata (P < .001, by the log-rank test).

Figure 3

The time from HAART initiation to achievement of a CD4⁺ count >500 cells/mm³, estimated using Kaplan-Meier techniques. Patients were stratified on the basis of their CD4⁺ cell counts before initiation of therapy (101, 72, 67, 50, and 60 patients had CD4⁺ cell counts of ≤100, 101−200, 201−300, 301−400, and >400 cells/mm³, respectively). The time from HAART initiation to achievement of a CD4⁺ cell count >500 cells/mm³ was significantly different among the strata (P < .001, by the log-rank test).

Figure 4

The percentage of patients with a CD4⁺ cell count in the normal range (>500 cells/mm³) over time, stratified by CD4⁺ cell count before initiation of therapy. Patients were censored after year 4 when plasma HIV RNA levels increased to >1000 copies/mL for any reason.