Definition of Immunological Nonresponse to Antiretroviral Therapy: A Systematic Review

Rb-Silva, Rita; Goios, Ana; Kelly, Christine; Teixeira, Pedro; João, Cristina; Horta, Ana; Correia-Neves, Margarida

doi:10.1097/qai.0000000000002157

Cited by 43 publications

(39 citation statements)

References 124 publications

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“…Immunological nonresponse denotes a CD4 + cell count <350 cells/μl despite ART and viral suppression [32]. In our virally suppressed cohort, we found that a CD4 + cell count <350 cells/μl at study entry was associated with de novo PAD, suggesting that immunological nonresponders may potentially be at higher risk.…”

Section: Discussionmentioning

confidence: 66%

High incidence of subclinical peripheral artery disease in people with HIV

Suarez-Zdunek

Høgh

Kirkegaard-Klitbo

et al. 2022

Aids

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Objective:Atherosclerosis is common in people with HIV (PWH). Peripheral artery disease (PAD) is the peripheral manifestation of atherosclerosis, but little is known about the incidence of PAD in PWH. Our objective was to determine the PAD incidence in PWH and to investigate potential risk factors.Design:Prospective longitudinal study on PWH from the Copenhagen Comorbidity in HIV Infection (COCOMO) study cohort.Methods:We performed ankle-brachial index (ABI) measurements at study entry and at 2-year follow-up and included participants with normal ABI at study entry. We defined de novo PAD as ABI ≤0.9 at follow-up. Using Poisson regression adjusted for age, sex, and smoking, we investigated the role of traditional and HIV-related risk factors, including inflammatory markers.Results:Of 844 PWH followed for a median duration of 2.3 years, 30 (3.6%) developed de novo PAD. All cases were subclinical. Diabetes (relative risk [RR] = 4.90 [95% confidence interval [CI]: 1.99–12.1]), current CD4+ cell count <350 cells/μl (2.66 [1.06–6.71]), longer duration of antiretroviral therapy (antiretroviral therapy [ART], 1.88 [1.06–3.33] per decade), and concentrations of high-sensitivity C-reactive protein (1.33 [1.08–1.63] per doubling) and interleukin-6 (1.38 [1.06–1.80] per doubling), were associated with de novo PAD.Conclusions:PWH had a high incidence of de novo subclinical PAD. Diabetes, low current CD4+ cell count, duration of ART, and inflammatory markers were associated with de novo PAD, indicating a possible role in PAD pathogenesis in PWH.

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Section: Discussionmentioning

confidence: 66%

High incidence of subclinical peripheral artery disease in people with HIV

Suarez-Zdunek

Høgh

Kirkegaard-Klitbo

et al. 2022

Aids

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“…Although plasma viral load declines to undetectable levels after initiation of antiretroviral therapy (ART), immune reconstitution may not occur; about 10–40% of HIV-infected individuals fail to normalize CD4 + T cell counts. These patients, known as immunological non-responders (INRs), have severe immune dysfunction with CD4 + T cell counts < 500 or < 350 cells/μL, or in extreme cases, < 200 cells/μL [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Association between CD4+ T cell counts and gut microbiota and serum cytokines levels in HIV-infected immunological non-responders

Zhang

Wang

et al. 2021

BMC Infect Dis

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Background CD4+ T cell counts in certain human immunodeficiency virus (HIV)-infected patients called immunological non-responders (INRs) could not return to a normal level even with sustained antiretroviral therapy (ART) because of persistent immune activation, which is associated with pro-inflammatory cytokines production and an altered intestinal microbiome profile. Changes in gut bacterial composition have been linked to low CD4+ T cell counts in HIV-infected individuals. However, the association between CD4+ T cell counts and gut microbiota community composition and cytokines levels in INRs (CD4+ T cell counts < 500 cells/μL) from Yunnan Province, China, has not been previously investigated. Methods To address this issue, we carried out a cross-sectional study of 34 HIV-infected INRs. The patients were divided into CD4 count > 200 cells/μL group and CD4 count < 200 cells/μL group. The gut microbiota composition of each subject was analyzed by 16S rRNA gene sequencing. We also compared CD8+ T cell counts, pro-inflammatory cytokines levels, and nutritional status between the two groups. Results Compared to INRs with CD4 count > 200 cells/μL, those with CD4 count < 200 cells/μL had a lower CD4/CD8 ratio, lower nutritional status and higher serum levels of tumor necrosis factor (TNF)-α, interferon-γ-inducible protein (IP)-10 and interleukin (IL)-1α. Ruminococcaceae was less abundant in the CD4 count < 200 cells/μL group than in the CD4 count > 200 cells/μL group, and difference in alpha diversity was observed between the two groups. Moreover, CD4+ T cell counts were negatively associated with TNF-α and IL-1α levels and positively associated with the relative abundance of Ruminococcaceae. Conclusions Our study demonstrated that lower CD4+ T cell counts in INRs are associated with a reduced abundance of Ruminococcaceae in the gut and elevated serum pro-inflammatory cytokines levels. Thus, interventions targeting gut microbiota to increase CD4+ T cell counts are a potential strategy for promoting immune reconstitution in HIV-infected INRs.

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“…Of the selected subjects, 120 were considered controls (baseline CD4 + T-cell counts >200 cells/µL), and 101 were cases (baseline CD4 + T-cell counts ≤ 200 cells/µL). At 144 weeks, cases were classified according to the cut-off of 250 CD4 + T cells [2,57]. Among the cases, 77 subjects (76.2%) achieved a value of more than 250 CD4 + T cells/µL after 144 weeks of ART ("immunological recoverers", IR), whereas 22 subjects (21.8%) did not reach the 250 CD4 + T cells/µL threshold ("immunological nonrecoverers", INRs).…”

Section: Study Design and Participantsmentioning

confidence: 99%

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy

Yeregui

Masip

Viladés

et al. 2022

IJMS

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A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response.

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Definition of Immunological Nonresponse to Antiretroviral Therapy: A Systematic Review

Cited by 43 publications

References 124 publications

High incidence of subclinical peripheral artery disease in people with HIV

High incidence of subclinical peripheral artery disease in people with HIV

Association between CD4+ T cell counts and gut microbiota and serum cytokines levels in HIV-infected immunological non-responders

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy

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