Risk of Severe Non AIDS Events Is Increased among Patients Unable to Increase their CD4+ T-Cell Counts >200+/μl Despite Effective HAART.

Giuseppe Lapadula,Angelo Pan,Andrea Gori,Laura Sighinolfi,Simona Di Giambenedetto,Emanuele Focà,Carlo Torti,Italian Master Cohort ,Nicoletta Ladisa,Francesco Castelli,Massimiliano Fabbiani,Liliane Chatenoud,Massimo Di Pietro,Franco Maggiolo

doi:10.1371/journal.pone.0124741

Abstract

BackgroundImmunological non-response (INR) despite virological suppression is associated with AIDS-defining events/death (ADE). Little is known about its association with serious non-AIDS-defining events (nADE).MethodsPatients highly-active antiretroviral therapy (HAART) with <200 CD4+/μl and achieving HIV-RNA <50 copies/ml within 12 (±3) months were categorized as INR if CD4+ T-cell count at year 1 was <200/μl. Predictors of nADE (malignancies, severe infections, renal failure—ie, estimated glomerular filtration rate <30 ml/min, cardiovascular events and liver decompensation) were assessed using multivariable Cox models. Follow-up was right-censored in case of HAART discontinuation or confirmed HIV-RNA>50.Results1221 patients were observed for a median of 3 (IQR: 1.3-6.1) years. Pre-HAART CD4+ were 77/μl (IQR: 28-142) and 56% of patients had experienced an ADE. After 1 year, CD4+ increased to 286 (IQR: 197-387), but 26.1% of patients were INR. Thereafter, 86 nADE (30.2% malignancies, 27.9% infectious, 17.4% renal, 17.4% cardiovascular, 7% hepatic) were observed, accounting for an incidence of 1.83 events (95%CI: 1.73-2.61) per 100 PYFU. After adjusting for measurable confounders, INR had a significantly greater risk of nADE (HR 1.65; 95%CI: 1.06-2.56). Older age (per year, HR 1.03; 95%CI: 1.01-1.05), hepatitis C co-infection (HR 2.09; 95%CI: 1.19-3.7), a history of previous nADE (HR 2.16; 95%CI: 1.06-4.4) and the occurrence of ADE during the follow-up (HR 2.2; 95%CI: 1.15-4.21) were other independent predictors of newly diagnosed nADE.ConclusionsPatients failing to restore CD4+ to >200 cells/μl run a greater risk of serious nADE, which is intertwined or predicted by AIDS progression. Improved management of this fragile population and innovative therapy able to induce immune-reconstitution are urgently needed. Also, our results strengthen the importance of earlier diagnosis and HAART introduction.

Highlights

The introduction of highly active anti-retroviral therapy (HAART) among patients formerly naïve to treatment leads to the suppression of HIV replication in most cases.[1]
Older age, hepatitis C co-infection (HR 2.09; 95%CI: 1.19-3.7), a history of previous non AIDS-defining events (nADE) (HR 2.16; 95% CI: 1.06-4.4) and the occurrence of AIDS-defining events/death (ADE) during the follow-up (HR 2.2; 95%CI: 1.15-4.21) were other independent predictors of newly diagnosed nADE
These results are in agreement with a recent study that demonstrated that patients unable to restore their CD4+ count to >200 cells/μl after 3 years of viral suppression run a higher risk of death due to non AIDS-defining causes

Summary

Introduction

The introduction of highly active anti-retroviral therapy (HAART) among patients formerly naïve to treatment leads to the suppression of HIV replication in most cases.[1] a variable proportion of subjects, ranging from 6 to 20%, commonly referred to as “immunological non responders” (INR), fail to achieve a significant immune recovery, as measured by peripheral CD4 cell count, despite virological response to HAART.[2,3,4,5,6,7]. Little is known about its association with serious nonAIDS-defining events (nADE)

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