Influence of the Timing of Antiretroviral Therapy on the Potential for Normalization of Immune Status in Human Immunodeficiency Virus 1–Infected Individuals The goal of antiretroviral therapy (ART) in patients with human immunodeficiency virus-1 (HIV-1) infection has focused primarily on achieving an undetectable plasma HIV viral load (VL), because failure to achieve this virologic landmark is associated with highly impaired immune recovery.1-3 Durable VL suppression is readily attainable with potent and well-tolerated ART, shifting attention to the goal of optimal reconstitution of a severely compromised immune system, which is the central pathogenic feature of HIV infection.1,4-7 However, a specific CD4+ T-cell count as a target for optimal immunologic health has not been validated, nor has an interval from infection to ART initiation that promotes this goal been established. In clinical practice, an increase in the CD4+ count to 500 cells/μL or higher while receiving ART is typically regarded as optimal immune recovery.2,8-10 However, our group 11 previously showed that in individuals without HIV infection, the median CD4+ count is approximately 900 cells/μL. This observation raised the possibility that HIV-infected persons with CD4+ counts less than 900 cells/μL while receiving VLsuppressive ART may remain immunologically compromised. Substantiating this finding, individuals with CD4+ counts between 500 and 750 cells/μL who are receiving ART have an increased risk of AIDS compared with those having higher CD4+ counts.12 In the present study, we tested the hypothesis that normalization of CD4+ counts (≥900 cells/μL), compared with attainment of lower CD4+ counts during VL-suppressive ART, is associated with (1) mitigated AIDS risk; (2) reduced T-cell activation and exhaustion, which are factors predictive of adverse clinical outcomes (death, AIDS, and non-AIDS comorbidities)1,12-14; and (3) enhanced T-cell responsiveness to T-cell trophic cytokines such as interleukin 7 (IL-7), a key player in T-cell homeo stasis.15 We tested our hypothesis in the US Military HIV Natural History Study (NHS), a large observational cohort of individuals with HIV infection in which most participants have estimated dates of sero conversion (EDS).16-19 The results of the study in the NHS cohort affirmed our hypothesis, prompting us to identify actionable items that physicians and public health policymakers could undertake to facilitate and promote CD4+ normalization. Earlier vs later ART is traditionally defined by whether ART is initiated before or after CD4+ counts have declined below a specific threshold(eg, 500 cells/μL), rather than the duration of HIV infection before initiation of ART.2,3,20,21 However, our group’s 11 prior analyses of the San Diego Primary HIV Infection Cohort indicated that initiating ART as soon as possible after acquiring HIV, especially within 12 months of infection, greatly promoted CD4+ normalization. Few patients seek care during primary HIV infection. Thus, to validate as well as to extend our group’s 11 previous finding made in a primary infection cohort to a more real-life clinical setting, we examined participants in the NHS and determined whether initiating ART after 12 months of the EDS and/or study entry was associated with 4 primary outcomes: reduced CD4+ normalization, increased AIDS risk, increased T cell activation, and impaired in vivo functional immune responses. Earlier ART and CD4+ Normalization The conceptual framework for the remainder of the study is depicted in Figure 3A, which shows both the CD4+ trajectory and specific time intervals from infection within which initiation of ART was associated with improved CD4+ normalization rates in a primary infection cohort: 4 or 12 months from infection for participants startingARTwithCD4+ counts of less than 500 cells/μL or 500 cells/μL or more, respectively.11However, theEDS, but not date of infection, was knownin theNHS cohort, and the number of NHS participants accruedwithin 4 months of acquiring HIV infection was likely to be very low. Therefore, in the present study,we used an interval of less than or equal to 12 months and more than 12 months between EDS or study entry and ART initiation as a classifier for earlier vs later ART. Consistent with our prior work,11 a CD4+ count of 500 cells/μL at study entry or before ART initiation was used to classify higher vs lower CD4+ counts, because it is used as a threshold for initiation ofART inmost international HIV treatment guidelines.2,3 The median interval between the EDS and study entrywas approximately 10 months; ART was initiated in 26.1%or 57.6% of the patients at 12 months or less from the EDS or study entry, respectively (Table 1). Earlier comparedwith laterART was associatedwith a significantly shorter time to VL suppression. The proportion of participants achieving CD4+ normalization was significantly greater in those starting ART earlier comparedwiththose initiatingARTlater, indexedtotheEDS (38.4% vs 28.3%; P = .001) or study entry (35.4%vs 24.9%; P < .001). In univariate analyses, ART timing indexed to either the EDS or study entry, CD4+ count at study entry or pre-ART, calendar year of ART initiation, ART regimen, duration of VLsuppressiveART, and time fromART initiation toVL suppressionwere associatedwith CD4+ normalization rates (Table 2). Earlier compared with later ART indexed to the EDS or study entry and higher compared with lower CD4+ counts at entry or pre-ART were each associated with increased CD4+ normalization rates, after controlling for covariates (Table 2, models 1-4). Participants were initially stratified into 4 sets based on the change in CD4+ counts between study entry and ART initiation referenced to a CD4+ threshold of 500 cells/μL (Figure 3B), and then into 8 subsets based on whether ART was initiated earlier vs later indexed to the EDS (Figure 3C and D) or study entry (eFigure 2 in the Supplement). In general, there was an additive effect of later ART and lower CD4+ counts at study entry and/or pre-ART on depressing CD4+ normalization rates, resulting in a hierarchal pattern of these rates (Figure 3C and D and eFigure 2 in the Supplement). First, among participants with study entry CD4+counts of less than 500 cells/μL, earlier ART did not substantially improve CD4+ normalization rates, whereas it did so among participants with entry CD4+ counts of 500 cells/μL or more. Second, among participants with entry CD4+ counts of less than 500 cells/μL, those manifesting a spontaneous rebound to 500 cells/μL or more and having ART initiated at these higher CD4+ levels had higher CD4+ normalization rates. To parse further the effects of progressively increasing durations of untreated infection on the likelihood of CD4+ normalization, we stratified the 4 CD4+-defined sets shown in Figure 3B into 12 subsets (subsets 1′-12′ in Figure 4). Participantswere categorizedaccording towhether they initiatedART earlier or later co-indexed to the EDS and study entry; that is, whetherARTwas startedwithin 12months of both theEDS and study entry (earlier/earlier [E/E]), after 12months fromtheEDS but within 12 months of study entry (later/earlier [L/E]), and after 12 months from both the EDS and study entry (later/ later [L/L]) (Figure 4). The time to ART initiation, referenced from the EDS or study entry, was progressively longer in the E/E, L/E, and L/L subsets (Figure 4). The shortest interval between the EDS and study entry was in the E/E subsets (median range, 4.0-6.7 months). Among these 12 subsets, the percentage achieving CD4+ normalization was highest in the E/E, L/E, and L/L subsets in participants with CD4+ counts of 500 cells/μL or more at both study entry and pre-ART (subsets 1′ to 3′), and this was followed by the E/E subsets in participants with study entry CD4+ counts of 500 cells/μL or more but pre-ART values of less than 500 cells/μL (subset 4′) and study entry CD4+ counts of less than 500 cells/μL but pre-ART values of 500 cells/μL or more (subset 7′). The pre-ART CD4+ counts in the E/E, L/E, and L/L subsets in participants with CD4+ counts of 500 cells/μL or more at both study entry and pre-ART were similar (approximately 600 cells/μL) (subsets 1′-3′ in Figure 4). The CD4+ count at ART initiation was an imperfect indicator of the duration of infection, as the median intervals between the EDS and ART initiation in the E/E, L/E, and L/L subsets were 6.8, 16.5, and 55.6 months, respectively (subsets 1′-3′ in Figure 4). The odds of CD4+ normalization were lower by 65% in the L/E subset (adjusted OR [aOR], 0.35; 95% CI, 0.12-1.04; P = .06) and 80% in the L/L (aOR, 0.20; 95% CI, 0.07-0.53; P = .001) subset compared with the E/E subset, after controlling for covariates, including 10 cells/μL differences in pre-ART CD4+ counts (subsets 2′ and 3′ vs subset 1′ in Figure 4). These data indicate that it was not the numeric
Posted on: Sat, 29 Nov 2014 12:57:34 +0000
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