Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression

Ndumbi, Patricia; Falutz, Julian; Pai, Nitika Pant; Tsoukas, Christos

doi:10.1371/journal.pone.0094018

Cited by 21 publications

(21 citation statements)

References 37 publications

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“…count and current CD4:CD8 ratio, which has not been reported in previous smaller studies in children [5]. While different study designs and different definitions of a 'normal' CD4:CD8 ratio make direct comparisons difficult, in two adult studies in which the length of time on ART was comparable to that in this study, there were still considerably lower rates of ratio normalization (37% and 16%, respectively) [13,14]. However, nadir CD4 counts were lower in both adult cohorts (medians 130 cells/lL and 157 and 136 cells/lL for the CD4:CD8 ≥ 0.9 and < 0.9 groups, respectively) compared with this cohort (median 425 cells/lL).…”

Section: Discussioncontrasting

confidence: 69%

CD4:CD8 ratio in children with perinatally acquired HIV‐1 infection

et al. 2018

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ObjectivesIn adults with horizontally acquired HIV infection, an inverted CD4:CD8 ratio is associated with persistent immune activation, size of HIV reservoir and predicts an increased risk of non‐AIDS‐defining adverse events. Normalization of this ratio with antiretroviral therapy (ART) is suboptimal in adults, despite viral suppression, and is less well described in paediatric populations. We investigated rates of CD4:CD8 ratio recovery in children with perinatally acquired HIV infection (PaHIV) on ART.MethodsA cross‐sectional, retrospective analysis of routine clinical data in children with PaHIV (5–18 years old) attending a single UK centre was carried out.Results CD4:CD8 normalization was seen in 62% of children on suppressive ART. A negative correlation was found between current CD4:CD8 ratio and age at start of ART. Positive correlations were found between current CD4:CD8 ratio and total time with suppressed HIV viral load and nadir CD4 counts. Multiple linear regression analysis showed that age at start of ART was significantly associated with current CD4:CD8 ratio (standardized β = −0.680; P < 0.001). Patient sex, ethnicity and antiretroviral regimen did not affect ratio recovery.ConclusionsWe found higher rates of CD4:CD8 ratio normalization compared with previous adult studies. Children who started ART at a younger age were more likely to recover a normal ratio. The current policy of universal treatment for all HIV‐positive adults and children will enhance immunological normalization.

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Section: Discussioncontrasting

confidence: 69%

CD4:CD8 ratio in children with perinatally acquired HIV‐1 infection

et al. 2018

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“…In conclusion, the importance of timely initiation of cART before profound immunodeficiency occurs in children should not be underestimated, as has been reported previously [9], [11], [12], [13], [14]. The Ministry of Health in Rwanda has recognized this and has adjusted its guidelines accordingly.…”

Section: Discussionmentioning

confidence: 74%

Safety and Effectiveness of Combination Antiretroviral Therapy during the First Year of Treatment in HIV-1 Infected Rwandan Children: A Prospective Study

et al. 2014

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BackgroundWith increased availability of paediatric combination antiretroviral therapy (cART) in resource limited settings, cART outcomes and factors associated with outcomes should be assessed.MethodsHIV-infected children <15 years of age, initiating cART in Kigali, Rwanda, were followed for 18 months. Prospective clinical and laboratory assessments included weight-for-age (WAZ) and height-for-age (HAZ) z-scores, complete blood cell count, liver transaminases, creatinine and lipid profiles, CD4 T-cell count/percent, and plasma HIV-1 RNA concentration. Clinical success was defined as WAZ and WAZ >−2, immunological success as CD4 cells ≥500/mm3 and ≥25% for respectively children over 5 years and under 5 years, and virological success as a plasma HIV-1 RNA concentration <40 copies/mL.ResultsBetween March 2008 and December 2009, 123 HIV-infected children were included. The median (interquartile (IQR) age at cART initiation was 7.4 (3.2, 11.5) years; 40% were <5 years and 54% were female. Mean (95% confidence interval (95%CI)) HAZ and WAZ at baseline were −2.01 (−2.23, −1.80) and −1.73 (−1.95, −1.50) respectively and rose to −1.75 (−1.98, −1.51) and −1.17 (−1.38, −0.96) after 12 months of cART. The median (IQR) CD4 T-cell values for children <5 and ≥5 years of age were 20% (13, 28) and 337 (236, 484) cells/mm3respectively, and increased to 36% (28, 41) and 620 (375, 880) cells/mm3. After 12 months of cART, 24% of children had a detectable viral load, including 16% with virological failure (HIV-RNA>1000 c/mL). Older age at cART initiation, poor adherence, and exposure to antiretrovirals around birth were associated with virological failure. A third (33%) of children had side effects (by self-report or clinical assessment), but only 9% experienced a severe side effect requiring a cART regimen change.ConclusionscART in Rwandan HIV-infected children was successful but success might be improved further by initiating cART as early as possible, optimizing adherence and optimizing management of side effects.

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“…Ndumbi et al monitored the longitudinal changes in CD4:CD8 ratio over a 10-year follow-up in ART treated patients [23]. They demonstrated that in patients with a CD4 T cell count B 200 cells/mm 3 , the CD4:CD8 ratio failed to normalize.…”

Section: Resultsmentioning

confidence: 99%

CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV‐positive patients

Lü¹,

Mehraj²,

Vyboh³

et al. 2015

Journal of the International AIDS Society

184

129

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IntroductionAbsolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long-term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long-term treated patients.MethodWe conducted a comprehensive literature review of publications in English language using major electronic databases. Our search was focused on factors contributing to CD4:CD8 T cell ratio and clinical outcome in adult HIV-positive patients in the context of treated infection.DiscussionLow CD4:CD8 ratio has been linked to ageing and acts as a predictor of mortality in the general population. This ratio may represent the combined effects of inflammation and immunological changes called “inflammaging.” Although the mechanisms underlying partial correction of the CD4:CD8 ratio and persistently elevated CD8 T cell count in long-term treated patients remain poorly understood, it has been recently indicated that patients with optimal CD4 T cell recovery and low CD4:CD8 ratio still harbour increased immune activation, an immune senescent phenotype and have a higher risk of non-AIDS morbidity and mortality. This review reconsiders CD4:CD8 ratio in the light of advances in the understanding of immune dysfunction and examines its pathophysiological features and implications on clinical outcome and HIV reservoir size in long-term treated HIV-positive adults.ConclusionThe CD4:CD8 ratio can contribute to the immunological evaluation of treated patients in a long-term follow-up and may be applied for monitoring both immune dysfunction and viral reservoir size in immune-based clinical trials.

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Delay in cART Initiation Results in Persistent Immune Dysregulation and Poor Recovery of T-Cell Phenotype Despite a Decade of Successful HIV Suppression

Cited by 21 publications

References 37 publications

CD4:CD8 ratio in children with perinatally acquired HIV‐1 infection

CD4:CD8 ratio in children with perinatally acquired HIV‐1 infection

Safety and Effectiveness of Combination Antiretroviral Therapy during the First Year of Treatment in HIV-1 Infected Rwandan Children: A Prospective Study

CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV‐positive patients

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