Pre-cART Elevation of CRP and CD4+ T-Cell Immune Activation Associated With HIV Clinical Progression in a Multinational Case–Cohort Study

Abstract

Background Despite the success of combination antiretroviral therapy (cART), a subset of HIV-infected patients who initiate cART develop early clinical progression to AIDS; therefore some cART initiators are not fully benefitted by cART. Immune activation pre-cART may predict clinical progression in cART initiators. Methods A case-cohort study (n=470) within the multinational Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS) clinical trial (1571 HIV treatment-naïve adults who initiated cART; CD4+ T cell count <300 cells/mm3; nine countries) was conducted. A subcohort of 30 participants/country was randomly selected; additional cases were added from the main cohort. Cases (n=236 [random subcohort–36; main cohort–200]) had clinical progression (incident WHO Stage 3/4 event or death) within 96 weeks following cART initiation. Immune activation biomarkers were quantified pre-cART. Associations between biomarkers and clinical progression were examined using weighted multivariable Cox-proportional hazards models. Results Median age was 35 years, 45% were women, 49% black, 31% Asian, and 9% white. Median CD4+ T-cell count was 167 cells/mm3. In multivariate analysis, highest quartile CRP concentration (adjusted hazards ratio [aHR] 2.53, 95%CI 1.02-6.28) and CD4+ T-cell activation (aHR 5.18, 95CI 1.09-24.47) were associated with primary outcomes, compared to lowest quartiles. sCD14 had a trend towards association with clinical failure (aHR 2.24, 95%CI 0.96–5.21). Conclusions Measuring CRP and CD4+ T-cell activation may identify patients with CD4+ T cell counts < 300 cells/mm3 at risk for early clinical progression when initiating cART. Additional vigilance and symptom-based screening may be required in this subset of patients even after beginning cART.

Immunologic Pathways That Predict Mortality in HIV-Infected Ugandans Initiating Antiretroviral Therapy

“…Lower CD4 + T-cell counts may potentially confound the association between T-cell activation and mortality or could represent a true causal association between T-cell activation and mortality, which would largely be mediated by greater CD4 + T-cell depletion. This latter interpretation would be consistent with findings from the recent ACTG PEARLS study, conducted in low-income and middle-income countries, in which pre-ART CD4 + T-cell immune activation predicted early clinical progression, even after adjustment for CD4 + T-cell count [3]. There was a notable lack of association between certain biomarkers and mortality in our cohort.…”

“…A total of 457 participants achieved viral suppression by month 6 of ART, with a median CD4 + T-cell count of 242 cells/ mm 3 . Forty-four deaths occurred during a median of 7 years of follow-up; 36 were due to illness/disease, while 8 were due to unknown causes (but not trauma/injury, suicide, or a cause related to childbirth).…”

“…IL-6 was less predictive of mortality than pre-ART T-cell activation in the international PEARLS study [3]. Our group recently reported that the KT ratio predicts mortality more strongly than T-cell activation in Ugandans with ART-suppressed HIV infection [4] and to a greater degree than observed in North American studies [5,6].…”

Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort

“…The microbial translocation marker lipopolysaccharide shared the same pattern of decrease without normalization [29]. IL-6, one of the strongest predictors of mortality and AIDS in untreated HIV-infected patients and in patients initiating ART, did not change appreciably during ART [30–32], a finding underscored by us here and previously [33]. Although several immune activation markers have been characterized pre-ART, few studies have examined how continued immune activation during ART affects treatment outcome, particularly in resource-constrained countries, from where the majority of study population was recruited.…”

Influence of Lymphocyte T CD4 Levels on the Neuropsychological Performance of Population A ected by HIV and with a Previous History of Substance Use

“…As far as immunological markers are concerned, the lymphocyte T CD4 rate of decrease is a good indicator to determine the probability of developing AIDS [2] [27] [36], however, its efficiency to predict neurological and neuropsychological affectation has not been confirmed. While some authors point out that the probability of developing neuropsychological affectation is higher among seropositive patients with low levels of lymphocytes CD4 [26] For all these reasons, the objective of this article is to study the connection between lymphocytes T CD4 levels and the neuropsychological performance of former seropositive drug addicts.…”