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Brief Report: Enhanced Normalization of CD4/CD8 Ratio With Earlier Antiretroviral Therapy at Primary HIV Infection
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from Jules: deferring therapy in early days of HAART has put patients in a situation with very bad immunity leading to earlier & accelerated aging, comorbidities, frailty and increased risk for earlier mortality/death.
"Disruption of T-cell homeostasis by HIV induces CD4+ depletion and CD8+ T-cell expansion, resulting in an inverted CD4/CD8 ratio.13,14 Low CD4/CD8 ratio in individuals on suppressive ART has been independently associated with persistently elevated markers of T-cell activation8 and measures of HIV viral reservoirs.15,16 In untreated HIV infection, CD4/CD8 ratio inversely correlates with marker of T-cell activation and exhaustion.17 In addition, low CD4/CD8 ratio independently predicts all-cause mortality and non-AIDS–related events.17 CD4/CD8 T-cell ratio may therefore better predict immune function than total CD4+ count alone17,18 and may contribute to the observed START trial result, identifying a significantly enhanced clinical outcome for individuals starting ART at CD4 counts >500 cells per cubic millimeter.19 Enhanced normalization of the CD4 T-cell count with ART initiated within 4 months of seroconversion has recently been demonstrated.20 We hypothesized that CD4/CD8 ratio recovery would also be enhanced after immediate ART initiation initiated in primary HIV infection (PHI). We examined the dynamics of immune recovery by combining data from 2 cohorts of individuals with well-estimated dates of HIV seroconversion.
In conclusion, CD4/CD8 ratio normalization, albeit rare when ART is started in chronic infection, is markedly enhanced with ART initiation in PHI, with a greater benefit the sooner ART is started......ART initiation within 6 months from seroconversion was significantly more likely to normalize [HR (95% CI) = 2.47 (1.67 to 3.67), P < 0.001] than those initiating later.....within 1 year from the date of starting ART, 129/275 (46.9%) individuals in the <6-month group normalized the CD4/CD8 ratio, compared with 16/127 (12.6%) individuals in the ≥6-month group...rapid ART initiation confers a significantly enhanced probability of immunological recovery......in light of the recent findings reported by the START study,19 ART initiation regardless of CD4 T-cell count will be recommended by all international guidelines,29 which will include immediate ART initiation in PHI.
.....Higher CD4/CD8 ratio at seroconversion was independently associated with lower risk of endpoint [adjusted hazard ratio (aHR) (95% CI) = 0.52 (0.32 to 0.82), P = 0.005], as was higher baseline CD4 count [aHR (95% CI) = 0.79 per 100 cell increase (0.71 to 0.86), P < 0.001].......We found strong evidence that those with longer time between PHI and ART initiation were less likely to achieve normal CD4/CD8 ratio [aHR (95% CI) = 0.98 per month increase (0.97 to 0.99), P < 0.001] after adjusting for confounding variables (including baseline HIV-1 Viral load and CD4 count). The only other significant covariate in the model was baseline CD4+ cell count with normalization more likely as count increased [HR = 1.12 (95% CI: 1.09 to 1.15) per 50 cells per cubic millimeter increase, P < 0.001]
Our findings demonstrate that ART initiated within 6 months from PHI markedly increases the likelihood of normalization of the CD4/CD8 ratio compared with later initiation of therapy, irrespective of baseline CD4 count. This is in agreement with Serrano-Villar et al.24 In addition, we found that the probability of achieving normalization of CD4/CD8 ratio is increased for each month closer to seroconversion ART is initiated. The normalization of CD4/CD8 ratio is relatively rapid with almost half of the individuals achieving this within 1 year of ART initiation. This finding is in contrast to the reported normalization rates of CD4/CD8 ratio in treated chronic HIV infection,3,10,11 where the chances of normalization within 1 year of ART initiation remain low and are comparable to those initiating ART ≥6 months in our study. Higher rates of CD4/CD8 ratio normalization have been reported in 2 studies of treated chronic infection, but only following up to a median of 10 years on ART.9,25
Although HIV-1 DNA was not measured for all individuals in this study, an analysis of a subset of individuals from the SPARTAC trial found an inverse correlation between HIV-1 DNA and CD4/CD8 ratio.37 As such, normalization of CD4/CD8 ratio may be a future valuable biomarker, which better predicts those individuals with a smaller HIV reservoir. This could inform an algorithm to identify optimal candidates for cure interventions or treatment interruption. Furthermore, if CD4/CD8 ratio reflects HIV reservoir size, then our data support the finding by other groups that treatment with ART at PHI may limit HIV reservoir size.38
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Brief Report: Enhanced Normalization of CD4/CD8 Ratio With Earlier Antiretroviral Therapy at Primary HIV Infection
JAIDS Sept 1 2016 - Thornhill, John MB, BCh, BAO; Inshaw, Jamie BSc; Kaleebu, Pontiano MBChB, PhD; Cooper, David MD, DSc; Ramjee, Gita PhD; Schechter, Mauro MD, PhD; Tambussi, Giuseppe MD; Fox, Julie MBChB, MD; Samuel, Miriam MBBS; Miro, Jose M. MD, PhD; Weber, Jonathan FRCP; Porter, Kholoud PhD; Fidler, Sarah MBBS, PhD
*Department of Medicine, Imperial College, London, United Kingdom;
Medical Research Council Clinical Trials Unit, University College London, London, United Kingdom;
Medical Research Council/Uganda Virus Research Institute Research Unit on AIDS, Entebbe, Uganda;
Kirby Institute University of New South Wales and Centre for Applied Medical Research, St Vincent's Hospital, Sydney, Australia;
‖HIV Prevention Unit, Medical Research Council, Durban, South Africa;
Projeto Praça Onze, Hospital Escola Sao Francisco de Assis, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil;
Division of Infectious Diseases, Ospedale San Raffaele, Milan, Italy;
**Department of HIV, Faculty of Medicine, Guys and St Thomas' NHS Trust/Kings College London, United Kingdom; and
Hospital Clinic - IDIBAPS, University of Barcelona, Barcelona, Spain.
Abstract
Background: Total CD4+ T-cell counts predict HIV disease progression but do not necessarily reflect normalization of immune function. CD4/CD8 ratio is a marker of immune dysfunction, a prognostic indicator for non-AIDS mortality, and reflects viral reservoir size. Despite antiretroviral therapy (ART), recovery of CD4/CD8 ratio in chronic HIV infection is incomplete; we hypothesize enhanced CD4/CD8 ratio recovery with earlier treatment initiation in recently infected individuals.
Methods: CD4+ count and CD4/CD8 ratio were analyzed using data from 2 cohorts: SPARTAC trial and the UK HIV Seroconverters Cohort where primary HIV infection (PHI) was defined as within 6 months from estimated date of infection. Using time-to-event methods and Cox proportional hazard models, we examined the effect of CD4/CD8 ratio at seroconversion on disease progression (CD4 <350 cells per cubic millimeter/ART initiation) and factors associated with time from ART initiation to CD4/CD8 normalization (ratio >1.0).
Findings: Of 573 seroconverters, 482 (84%) had abnormal CD4/CD8 ratios at HIV seroconversion. Individuals with higher CD4/CD8 ratio at seroconversion were significantly less likely to reach the disease progression endpoint [adjusted hazard ratio (aHR) (95% CI) = 0.52 (0.32 to 0.82), P = 0.005]. The longer the interval between seroconversion and ART initiation [HR (95% CI) = 0.98 per month increase (0.97, 0.99), P < 0.001], the less likely the CD4/CD8 ratio normalization. ART initiation within 6 months from seroconversion was significantly more likely to normalize [HR (95% CI) = 2.47 (1.67 to 3.67), P < 0.001] than those initiating later.
Interpretation: Most individuals presenting in PHI have abnormal CD4/CD8 ratios. The sooner the ART is initiated in PHI, the greater the probability of achieving normal CD4/CD8 ratio.
BACKGROUND
Total CD4+ T-cell count is a validated surrogate marker of disease progression for HIV/AIDS.1–3 Although the risk of AIDS-related illness and opportunistic disease is significantly reduced once CD4 counts have recovered to levels >350 cells per cubic millimeter,4–6 the risk of non-AIDS morbidity persists.7 Despite recovery of total CD4+ T-cell counts with antiretroviral therapy (ART), the CD4/CD8 ratio often fails to normalize (defined as >1) when ART is initiated in chronic infection8 where reported normalization of CD4/CD8 ratio ranges from 6% to 26.3%.3,9–11 A recent study from a large Italian cohort reported a normalization rate of 29.4% despite 5 years of viral suppression on ART.12
Disruption of T-cell homeostasis by HIV induces CD4+ depletion and CD8+ T-cell expansion, resulting in an inverted CD4/CD8 ratio.13,14 Low CD4/CD8 ratio in individuals on suppressive ART has been independently associated with persistently elevated markers of T-cell activation8 and measures of HIV viral reservoirs.15,16 In untreated HIV infection, CD4/CD8 ratio inversely correlates with marker of T-cell activation and exhaustion.17 In addition, low CD4/CD8 ratio independently predicts all-cause mortality and non-AIDS–related events.17 CD4/CD8 T-cell ratio may therefore better predict immune function than total CD4+ count alone17,18 and may contribute to the observed START trial result, identifying a significantly enhanced clinical outcome for individuals starting ART at CD4 counts >500 cells per cubic millimeter.19 Enhanced normalization of the CD4 T-cell count with ART initiated within 4 months of seroconversion has recently been demonstrated.20 We hypothesized that CD4/CD8 ratio recovery would also be enhanced after immediate ART initiation initiated in primary HIV infection (PHI). We examined the dynamics of immune recovery by combining data from 2 cohorts of individuals with well-estimated dates of HIV seroconversion.
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