C-Reactive Protein (CRP), Interferon Gamma-Inducible Protein 10 (IP-10), and Lipopolysaccharide (LPS) Are Associated with Risk of Tuberculosis after Initiation of Antiretroviral Therapy in Resource-Limited Settings

JAIDS Journal of Acquired Immune Deficiency Syndromes

et al. 2017

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Introduction Numerous micronutrients have immunomodulatory roles that may influence risk of tuberculosis (TB), but the association between baseline micronutrient deficiencies and incident TB after antiretroviral (ART) initiation in HIV-infected individuals is not well characterized. Methods We conducted a case-cohort study (n=332) within a randomized trial comparing three ART regimens in 1571 HIV treatment-naïve adults from nine countries. A subcohort of 30 patients was randomly selected from each country (n=270). Cases (n=77; main cohort=62, random subcohort=15) included patients diagnosed with TB by 96 weeks post-ART initiation. We determined pre-treatment concentrations of vitamin A, carotenoids, vitamin B6, vitamin B12, vitamin D, vitamin E, and selenium. We measured associations between pre-treatment micronutrient deficiencies and incident TB using Breslow-weighted Cox regression models. Results Median pre-treatment CD4+ T-cell count was 170 cells/mm3; 47.3% were female; and 53.6% Black. In multivariable models after adjusting for age, sex, country, treatment arm, prior TB, baseline CD4 count, HIV viral load, body mass index, and C-reactive protein, pre-treatment deficiency in vitamin A (adjusted hazard ratio, aHR 5.33, 95% confidence interval, CI 1.54–18.43) and vitamin D (aHR 3.66, 95%CI 1.16–11.51) were associated with TB post-ART. Conclusion In a diverse cohort of HIV-infected adults from predominantly low- and middle-income countries, deficiencies in vitamin A and vitamin D at ART initiation were independently associated with increased risk of incident TB in the ensuing 96 weeks. Vitamin A and D may be important modifiable risk factors for TB in high-risk HIV infected patients starting ART in resource-limited, highly-TB-endemic settings.

Section: Resultssupporting

confidence: 73%

Section: Methodsmentioning

confidence: 99%

Vitamin A and D Deficiencies Associated With Incident Tuberculosis in HIV-Infected Patients Initiating Antiretroviral Therapy in Multinational Case-Cohort Study

Tenforde

Dowdy

JAIDS Journal of Acquired Immune Deficiency Syndromes

et al. 2017

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“…Upon ART initiation, immune activation is only partially attenuated, and not equally among all people [9–12]. We hypothesized that a subset of immune activation biomarkers measurable in ART initiators would not be suppressed by ART and might predict clinical failure.…”

mentioning

confidence: 99%

Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort

Balagopal

Open Forum Infectious Diseases

Shivakoti

et al. 2016

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Background. We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings.Methods. We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4+ T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis.Results. Among 99 cases and 234 controls, median baseline CD4+ T-cell count was 181 cells/µL, and HIV RNA was 5.05 log10 cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27–7.20), sCD14 (IRR, 2.17; 95% CI, 1.02–4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01–0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated.Conclusions. Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.

“…In ACTG A5095, hsCRP did not differ by gender at baseline but higher levels were seen at week 96 in women compared to men (6mg/L vs 1.6mg/L, p=0.001), with an estimated shift in hsCRP by gender of 2.5 mg/L 22 . CRP has been studied extensively in HIV populations with reports of increased HIV progression 23,24 , HIV treatment failure 25 , increased cardiovascular disease 26 , tuberculosis 14 , and increased risk of maternal mortality 23 .…”

Section: Discussionmentioning

confidence: 99%

“…Markers of inflammation (TNF-α, IFN-γ, IL-6, IL-18, IP-10, CRP) and microbial translocation/immune activation (LPS, sCD14) were measured at baseline pre-cART initiation and at weeks 24 and 48 post-cART initiation. The methods for biomarker selection and measurement have been described previously 14 . In brief, we selected markers associated with accelerated HIV disease progression.…”

Section: Methodsmentioning

confidence: 99%

Sex-Related Differences in Inflammatory and Immune Activation Markers Before and After Combined Antiretroviral Therapy Initiation

Mathad

JAIDS Journal of Acquired Immune Deficiency Syndromes

Balagopal

et al. 2016

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Background Women progress to death at the same rate as men despite lower plasma HIV RNA (VL). We investigated sex-specific differences in immune activation and inflammation as a potential explanation. Methods Inflammatory and immune activation markers (IFN-γ, TNF-α, IL-6, IL-18, IP-10, CRP, LPS, sCD14) were measured at weeks 0, 24, and 48 post-cART in a random subcohort (n=215) who achieved virologic suppression in ACTG A5175 (PEARLS). Association between sex and changes in markers post-cART was examined using random effects models. Average marker differences and 95%CI were estimated using multivariable models. Results At baseline, women had lower median log10VL (4.93 vs 5.18 copies/mL, p=0.01), CRP (2.32 vs 4.62 mg/L, p=0.01), detectable LPS (39% vs 55%, p=0.04), and sCD14 (1.9 vs 2.3 mcg/mL, p=0.06) versus men. By week 48, women had higher IFN-γ (22.4 vs 14.9 pg/mL, p=0.05), TNF-α (11.5 vs 9.5 pg/mL, p=0.02), and CD4 (373 vs 323 cells/mm3, p=0.02). In multivariate analysis, women had greater increases in CD4 and TNF-α but less of a decrease in CRP and sCD14 compared to men. Conclusions With cART-induced viral suppression, women have less reduction in key markers of inflammation and immune activation compared with men. Future studies should investigate the impact of these sex-specific differences on morbidity and mortality.