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Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202.

ABSTRACT: BACKGROUND:The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear. METHODS:A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin-6 (IL-6), soluble receptors of tumor necrosis factor ? (sTNF)-RI, sTNF-RII, TNF-?, soluble vascular cellular adhesion molecules (sVCAM-1), and soluble intercellular adhesion molecules (sICAM-1) with times to AIDS and to non-AIDS events used Cox proportional hazards models. RESULTS:Analysis included 244 subjects; 85% men and 48% white non-Hispanic with median age 39 years, HIV-1 RNA of 4.6 log10 copies per milliliter, and CD4 of 240 cells per microliter. Overall, 13 AIDS events (9 opportunistic infections, 3 AIDS-cancers, and 1 recurrent bacterial pneumonia) and 18 non-AIDS events (6 diabetes, 4 cancers, 3 cardiovascular, and 5 pneumonias) occurred. Higher baseline IL-6, sTNF-RI, sTNF-RII, and sICAM-1 were significantly associated with increased risk of AIDS-defining events. Adjustment for baseline HIV-1 RNA did not change results, whereas adjusting for baseline CD4 count left only sTNF-RI and sICAM-1 significantly associated with increased risk. Time-updated values of IL-6, sTNFR-I and II, and sICAM-1 were also associated with an increased risk. For non-AIDS events, only higher baseline high-sensitivity C-reactive protein was significantly associated with increased risk, whereas higher IL-6 was marginally associated with higher risk. Analyses of time-updated biomarker values showed tumor necrosis factor ? to be significantly associated with increased risk, even after adjustment for antiretroviral therapy, and CD4 count or HIV-1 RNA. CONCLUSIONS:Higher levels of several inflammatory biomarkers were independently associated with increased risk of AIDS and non-AIDS events.

SUBMITTER: McComsey GA

PROVIDER: S-EPMC3943548 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202.

McComsey Grace A GA Kitch Douglas D Sax Paul E PE Tierney Camlin C Jahed Nasreen C NC Melbourne Kathleen K Ha Belinda B Brown Todd T TT Bloom Anthony A Fedarko Neal N Daar Eric S ES

Journal of acquired immune deficiency syndromes (1999) 20140201 2

<h4>Background</h4>The association of inflammatory biomarkers with clinical events after antiretroviral therapy initiation is unclear.<h4>Methods</h4>A5202 randomized 1857 treatment-naive subjects to abacavir/lamivudine or tenofovir-DF/emtricitabine with efavirenz or atazanavir/ritonavir. Substudy A5224s measured inflammatory biomarkers on subjects with available plasma from baseline and week 24 or 96. An exploratory analysis of the association of high-sensitivity C-reactive protein, interleukin ...[more]

PMID: 24121755

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Project description:HIV-1 infection leads to chronic inflammation and to an increased risk of non-AIDS mortality. Our objective was to determine whether AIDS-defining events (ADEs) were associated with increased overall and cause-specific non-AIDS related mortality after antiretroviral therapy (ART) initiation. We included HIV treatment-naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART-CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause-specific non-AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non-Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model. The adjusted hazard of overall non-AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause-specific non-AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause-specific non-AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL). In this large multi-centre cohort collaboration with standardized assignment of causes of death, non-AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non-AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival.

Project description:BackgroundHigh-throughput approaches are increasingly being used to identify genetic associations across multiple phenotypes simultaneously. Here, we describe a pilot analysis that considered multiple on-treatment laboratory phenotypes from antiretroviral therapy-naive patients who were randomized to initiate antiretroviral regimens in a prospective clinical trial, AIDS Clinical Trials Group protocol A5202.Participants and methodsFrom among 5 9545 294 polymorphisms imputed genome-wide, we analyzed 2544, including 2124 annotated in the PharmGKB, and 420 previously associated with traits in the GWAS Catalog. We derived 774 phenotypes on the basis of context from six variables: plasma atazanavir (ATV) pharmacokinetics, plasma efavirenz (EFV) pharmacokinetics, change in the CD4+ T-cell count, HIV-1 RNA suppression, fasting low-density lipoprotein-cholesterol, and fasting triglycerides. Permutation testing assessed the likelihood of associations being by chance alone. Pleiotropy was assessed for polymorphisms with the lowest P-values.ResultsThis analysis included 1181 patients. At P less than 1.5×10, most associations were not by chance alone. Polymorphisms with the lowest P-values for EFV pharmacokinetics (CYPB26 rs3745274), low-density lipoprotein -cholesterol (APOE rs7412), and triglyceride (APOA5 rs651821) phenotypes had been associated previously with those traits in previous studies. The association between triglycerides and rs651821 was present with ATV-containing regimens, but not with EFV-containing regimens. Polymorphisms with the lowest P-values for ATV pharmacokinetics, CD4 T-cell count, and HIV-1 RNA phenotypes had not been reported previously to be associated with that trait.ConclusionUsing data from a prospective HIV clinical trial, we identified expected genetic associations, potentially novel associations, and at least one context-dependent association. This study supports high-throughput strategies that simultaneously explore multiple phenotypes from clinical trials' datasets for genetic associations.

Dataset Information

Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202.

Publications

Associations of inflammatory markers with AIDS and non-AIDS clinical events after initiation of antiretroviral therapy: AIDS clinical trials group A5224s, a substudy of ACTG A5202.

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