Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Chéreau, Fanny; Madec, Yoann; Sabin, Caroline; Obel, Niels; Ruiz‐Mateos, Ezequiel; Chrysos, Georgios; Fidler, Sarah; Lehmann, Clara; Zangerle, Robert; Wittkop, Linda; Reiss, Peter; Hamouda, Osamah; Pérez, Vicente Estrada; Leal, Manuel; Mocroft, Amanda; Olalla, Patricia García de; Ammassari, Adriana; Monforte, Antonella d’Arminio; Mussini, Cristina; Segura, Ferrán; Castagna, Antonella; Cavassini, Matthias; Grabar, Sophie; Morlat, Philippe; Wit, Stéphane De; Lambotte, Olivier; Meyer, Laurence

doi:10.1371/journal.pone.0173893

Cited by 30 publications

(27 citation statements)

References 34 publications

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“… have reported in HIV controllers with a plasma viral load below 1000 copies/mL that the percentage of CD4 and CD8 T cells expressing the markers HLA‐DR and CD38 in the blood as well as in the GALT decreased after 24 weeks of ART. Accordingly, another study observed, also in controllers, that blips are associated with a drop in CD4/CD8 ratio, a global marker of immune activation . These observations fit with the hypothesis that reducing viral production at low levels may prevent immune activation.…”

Section: The Issue Of Inflammation and Immune Activationsupporting

confidence: 67%

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

et al. 2019

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Three‐drug combination antiretroviral therapy (ART) became available in 1996, dramatically improving the prognosis of people living with HIV. The clinical benefits of ART are due to the sustained viral load suppression and CD4 T cell gains. Major drawbacks of the first ART regimens were adverse events, and high pill burden, which led to the reduction of drug adherence resulting in frequent treatment discontinuations and the development of drug resistance. Due to increased viral potency of new antiretroviral drugs consideration of a two‐drug combination therapy repositioning occurred in an effort to reduce adverse events, drug‐drug interactions and cost, while maintaining a sustained antiviral effect. Various combinations of two‐drug regimens have been studied, and non‐inferiority compared to a three‐drug regimen has been shown only for some of them. In addition, a two‐drug combination regimen may not be suitable for every patient, especially those who are pregnant, those with tuberculosis or coexisting HBV infection. Furthermore no information has been generated concerning the secondary transmission of HIV from patients who have undetectable plasma viral load on two‐drug regimens. Additional studies of two‐drug combinations are also necessary to evaluate the debated existence of low viral replication in tissues and on immune activation. While there is no urgent need to routinely switch patients to two‐drug combination therapy, due to the availability of drug combinations without significant toxicities, dual regimens represent a suitable option that deserve long‐term evaluation before being introduced to clinical practice.

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Section: The Issue Of Inflammation and Immune Activationsupporting

confidence: 67%

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

et al. 2019

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“…In one multinational observational study of individuals followed from seroconversion (CASCADE), virus control (<500 copies RNA/mL) occurred in a small minority (1.4%) but once achieved was maintained in most (the probability of maintaining control over 20 years was 0.74) [ 11 ]. In a multicenter study of controllers (Collaboration of Observational HIV Epidemiological Research Europe [COHERE]), progression was rare and was predicted by a low CD4/CD8 ratio and intermittent viremia [ 67 ]; similar findings were noted in a French study [ 68 ]. In smaller pathogenesis-oriented studies, heightened inflammation and T-cell activation predated and often predicted virologic progression [ 17 , 69 , 70 ].…”

Section: Can We Learn Anything From Controllers Who Eventually Progrementioning

confidence: 76%

HIV control: Is getting there the same as staying there?

Goulder

Deeks

2018

PLoS Pathog

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In this brief review and perspective, we address the question of whether the immune responses that bring about immune control of acute HIV infection are the same as, or distinct from, those that maintain long-term viral suppression once control of viremia has been achieved. To this end, we describe the natural history of elite and post-treatment control, noting the lack of data regarding what happens acutely. We review the evidence suggesting that the two clinical phenotypes may differ in terms of the mechanisms required to achieve and maintain control, as well as the level of inflammation that persists once a steady state is achieved. We then describe the evidence from longitudinal studies of controllers who fail and studies of biologic sex (male versus female), age (children versus adults), and simian immunodeficiency virus (SIV) (pathogenic/experimental versus nonpathogenic/natural infection). Collectively, these studies demonstrate that the battle between the inflammatory and anti-inflammatory pathways during acute infection has long-term consequences, both for the degree to which control is maintained and the health of the individual. Potent and stringent control of HIV may be required acutely, but once control is established, the chronic inflammatory response can be detrimental. Interventional approaches designed to bring about HIV cure and/or remission should be nuanced accordingly.

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“…Few studies have examined the long-term outcome of LTNP and HIC patients [ 2 – 9 ]. Contrary to previous studies, we used competing-risk analysis to accurately estimate the risk of status loss while avoiding overestimation.…”

Section: Discussionmentioning

confidence: 99%

“…Although many definitions coexist [ 1 ], these patients are generally defined as either long-term non progressors (LTNP) or HIV controllers (HIC), depending on whether they are defined based on immunologic or virologic factors and on protection of AIDS-defining events in the absence of antiretroviral treatment. Few studies have focused on the long-term outcomes of such rare patients [ 2 – 9 ], who will become more difficult to identify as new treatment guidelines recommend treatment initiation as early as possible. Therefore the management of the individuals already identified with such status is an issue for both patients and caregivers [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Loss of long-term non-progressor and HIV controller status over time in the French Hospital Database on HIV - ANRS CO4

Grabar¹,

Selinger-Leneman²,

Abgrall³

et al. 2017

PLoS ONE

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ObjectivesWe studied the frequency and risk factors for loss of long-term non-progressor (LTNP) and HIV controller (HIC) status among patients identified as such in 2005 in the French Hospital Database on HIV (FHDH-ANRS CO4).MethodsWe selected patients who were treatment-naïve and asymptomatic in 2005 (baseline). Those with ≥8 years of known HIV infection and a CD4 cell nadir ≥500/mm3 were classified as LTNP and those with ≥10 years of known HIV infection and 90% of plasma viral load (VL) values ≤500 copies/ml in the absence of cART as HIC. cART initiation without loss of status and death from non AIDS-defining causes were considered as competing events.ResultsAfter 5 years of follow-up, 33% (95%CI; 27–42) of 171 LTNP patients and 17% (95%CI; 10–30) of 72 HIC patients had lost their status. In multivariable analyses, loss of LTNP status was associated with lower baseline CD4 cell counts and CD4/CD8 ratios. Only VL was significantly associated with loss of HIC status after adjustment for the baseline CD4 cell count, the CD4/CD8 ratio, and concomitant LTNP status. The hazard ratio for loss of HIC status was 5.5 (95%CI, 1.5–20.1) for baseline VL 50–500 vs ≤50 cp/mL, after adjustment for the baseline CD4 cell count.ConclusionsOne-third of LTNP and one-fifth of HIC patients lost their status after 5 years of follow-up, raising questions as to the possible benefits and timing of ART initiation in these populations.

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Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Cited by 30 publications

References 34 publications

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

Two‐drug vs. three‐drug combinations for HIV‐1: Do we have enough data to make the switch?

HIV control: Is getting there the same as staying there?

Loss of long-term non-progressor and HIV controller status over time in the French Hospital Database on HIV - ANRS CO4

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