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/μL; 18% (n = 149) had a poor CD4+ recovery (<50 cells/μL) 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 (≥50 cells/μL; rate = 2.7/100 personyears) (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.

Clonally expanded CD4 + T cells can produce infectious HIV-1 in vivo

“…The fact that cells carrying infectious proviruses can expand by cell division complicates the problem of eliminating all of the HIV-1 proviruses that make up the HIV-1 reservoir. The patient we describe had advanced HIV infection at presentation and, although clinically stable for a number of years without opportunistic infections, he never achieved robust CD4 recovery while undergoing cART; it is possible that overall, immune surveillance was weak in this patient because of the poor recovery of his T cells during cART (12,13), which may have impaired tumor surveillance. It is likely that only a fraction of the cells in the clone were producing virus at any given time, which could help the clone escape from HIV-1-specific immune surveillance.…”

mTOR as a multifunctional therapeutic target in HIV infection

“…Although HAART accounts for the significant decrease in AIDSrelated morbidity and mortality seen in recent years [21], an increased rate of AIDS-related complications such as neurocognitive disorders, nephropathy and malignancies are being observed in patients with poor initial CD4 + recovery and in patients with a CD4 + count higher than 200 cells per mm 3 [22,23]. This could be caused by prolonged viral persistence, chronic immune activation, incomplete immune reconstitution and/or accelerated immune senescence.…”

Immunosenescence and hurdles in the clinical management of older HIV-patients

“…[78][79][80][81][82][83] Some suggests that these finding may be linked with higher adherence in older patients, 78,[84][85] but other authors reported a higher risk of inadequate adherence in HIV patients who have other comorbidities and take other medications besides HAART. [86][87] While virological response seems not to be influenced by age, at least biologically, older patients have lower CD4C T-cell gain compared with younger persons, [88][89][90][91][92][93][94][95] even when adjusted for antiretroviral therapy regimens. This is particularly relevant considering that lower CD4 T-cell counts are not only linked to HIV-related opportunistic infections and malignancies, but also lead to higher risk of non-AIDS-related comorbidities, adding to the already elevated risk conferred by age.…”