Poor initial CD4+ recovery with antiretroviral therapy prolongs immune depletion and increases risk for AIDS and non-AIDS diseases

Abstract

Background: Low CD4+ increases risk for both AIDS- and non-AIDS-related morbidity and mortality. The magnitude of CD4+ recovery early after initial antiretroviral therapy (ART) is important in the ultimate duration of immune depletion.

Methods: We examined CD4+ recovery among 850 participants in the Community Program for Clinical Research on AIDS Flexible Initial Retrovirus Suppressive Therapies study with virologic suppression (ie, achieved an HIV RNA level <400 copies/mL) with 8 months of initial ART and determined subsequent risk for AIDS, non-AIDS diseases (non-AIDS cancers and cardiovascular, end-stage renal, and liver diseases), or death using Cox regression during a median 5-year follow-up.

Results: Mean pretreatment CD4+ was 221 cells/microL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/microL) after 8 months of effective ART, resulting in lower CD4+ over 5 years. Older age (hazard ratio 1.34/10 yrs, P = 0.003) and lower screening HIV RNA (hazard ratio 0.65 per log10 copies/mL higher, P = 0.001), but not screening CD4+, were associated with a poor CD4+ recovery. After 8 months of effective ART, 30 patients experienced the composite outcome of AIDS, non-AIDS, or death among participants with a poor CD4+ recovery (rate = 5.8/100 person-years) and 74 patients among those with an adequate recovery (>or=50 cells/muL; rate = 2.7/100 person-years) (adjusted hazard ratio = 2.24, P < 0.001). The risk of this composite outcome associated with a poor CD4+ recovery declined when ART was initiated at higher CD4+ counts (P < 0.01).

Conclusions: Impaired immune recovery, despite effective ART, results in longer time spent at low CD4+, thereby increasing risk for a broad category of HIV-related morbidity and mortality conditions.

FIGURE 1

CD4+ and HIV RNA response in FIRST study participants assessed at month 8.

FIGURE 2

CD4+ count over time stratified by initial CD4+ recovery with ART. Mean CD4+ count (with 95% CI) is plotted over 5 years of follow-up among FIRST participants with virologic suppression (HIV RNA <400 copies/mL) after 8 months of initial ART and stratified by a poor (<50 cells/μL rise) or adequate (≥50 cells/μL rise) CD4+ recovery at month 8. The numbers of participants at each time point are listed below.

FIGURE 3

Incidence of AIDS, non-AIDS disease, or death based on initial CD4+ recovery. Rate per 100 person-years (with 95% CI) of morbidity and mortality (defined as AIDS, non-AIDS diseases, or death) after 8 months of effective ART is plotted. Data are presented by CD4+ count recovery using 3 cutoffs: 25, 50, and 100 cells/μL. The relative higher morbidity and mortality among those with less initial CD4+ recovery is consistent across all 3 cutoffs. The numbers of participants from each category are also listed. “AIDS Criteria” were adapted from 1993 Centers for Disease Control and Prevention AIDS criteria to include additional conditions: invasive aspergillosis, bartonellosis, Chaga disease (American trypanosomiasis) of the central nervous system, disseminated herpes zoster, visceral leishmaniasis (kala-azar), Hodgkin lymphoma, non-Hodgkin lymphoma (all cell types), chronic intestinal microsporidiosis (>1 month), nocardiosis, extrapulmonary Penicillium marneffei, extrapulmonary Pneumocystis jirovecii, and Rhodococcus equi disease. Non-AIDS events include cardiovascular, renal, and liver disease and non–AIDS-defining malignancies.

FIGURE 4

Risk of AIDS, non-AIDS, or death stratified by pretreatment CD4+ count. The risk of morbidity and mortality (defined as AIDS, non-AIDS disease, or death) after 8 months of effective ART is presented and stratified by pretreatment screening CD4+ count. The numbers of participants, events, and rates per 100 person-years are provided. A poor CD4+ recovery (<50 cells/μL) at 8 months leads to higher rates of subsequent morbidity and mortality overall, compared with participants with an adequate CD4+ recovery (≥50 cells/μL), though this risk declines when ART is started at higher CD4+ counts. This is reflected in the decreasing HR estimates of risk for morbidity and mortality after a poor CD4+ cell recovery, with reference to an adequate recovery, as pretreatment CD4+ count increases. *HRs were adjusted for age, gender, race/ethnicity, coinfection with hepatitis B or C, prior AIDS event, randomized ART treatment strategy, and screening CD4+ and RNA level.