Discordant responses to cART in HIV-1 patients in the era of high potency antiretroviral drugs: clinical evaluation, classification, management prospects

Abstract

The goal of antiretroviral treatment (ART) in HIV-1 patients is immune reconstitution following control of viral replication. CD4+ cell number/proportions are a crude but essential correlate of immune reconstitution. Despite suppression of HIV replication, a fraction of ART-treated patients still fails to fully reconstitute CD4+ T cell numbers (immunological nonresponders, INRs). New drugs, regimens and treatment strategies led to increased efficacy, lower side effects and higher virological success rates in clinical practice. The multitude of described immune defects and clinical events accompanying INR opposed to the marginal effect of antiretroviral intensification or immunotherapy trials underline the need for continuing efforts at understanding the mechanisms that underlie INR. Here, we reassess INR definition, frequency, and the achievements of active clinical and translational research suggesting a shared definition for insufficient, partial and complete CD4+ cell number recovery thus improving homogeneity in patient selection and mechanism identification.

Keywords:

• Antiretroviral treatment
• cART
• CD4
• HIV
• immune reconstitution
• immunological nonresponder
• immunotherapy

Key issues

• The goal of antiretroviral treatment (ART) in HIV-1 patients is represented by immune reconstitution following control of viral replication. Despite high rates of virological suppression (>90%) in HIV naive patients in the most recent registrative trials (as well as in clinical practice), a fraction of treated patients still fails to reconstitute CD4 T-cell numbers to reasonable levels. These patients are usually defined as immunological nonresponders (INRs).

• A universally shared definition for INRs has not been achieved. Different authors adopted different definitions based on either absolute or proportional changes in CD4+ cell counts.

• The multitude of described immune defects and clinical events related to INRs opposed to the so far marginal effects of antiretroviral intensification or immunotherapy underline the need for continuing research in this field.

• INRs still maintain a higher mortality and morbidity rate due to AIDS and non-AIDS events compared to full responders; in particular the reduction of the risk in new AIDS events is continuously and directly related with CD4+ cell increase.

• ART intensification trials designed to control residual HIV replication in secondary lymphoid organs mainly rested on raltegravir or maraviroc. The majority of these trials failed to show a significant success in reverting INRs status albeit in the presence of some improvement in specific immunological findings (e.g. decrease in the frequency of activated CD4 and CD8 T cells and of T-cell apoptosis in both CD4/CD8 and a significant expansion of CD8 T cells with reduced immune activation).

• Epidemiological data on the incidence of INRs have not been recently updated. The increase in the CD4+ cell threshold for starting ART over the years (from 200 to 350 to 500/µl) may lead to an underestimation/decreased perception of INR or to its disappearance.

• The high incidence of late-presenter (according to CD4 cell numbers) or AIDS presenter patients, however, suggests that this issue will continue to represent a clinical challenge for physicians and patients and therefore deserves renewed focus.

• Age, clinical condition (AIDS or non-AIDS) at first HIV diagnosis, nadir CD4+ cells ever, cd4 and cd8 activation, Treg CD4+ cells and CD4/CD8r have been associated with an impaired immunological response. A (INR) classification which is taking into account these elements and defined changes in CD4+ cells is here proposed for clinical use, in order to support homogeneous and improved patient management.

Financial & competing interests disclosure

The authors were supported by Ministero della Salute RF-2010-2316197(ADM), Fondi Ateneo MIUR 2014. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.