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

Abstract

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.

Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study

“…In our prior analyses on the association of an individual marker with an outcome (CTF or TB) using this same dataset [ 6 , 7 , 46 ], specific markers that were independently associated (e.g., vitamin D) with the outcome do not have significant loadings on any of the dominant factors. However, it is important to note that it is possible for a specific marker to still be independently associated with an outcome despite not being a part of one of the extracted factors.…”

Impact of Vitamin A and Carotenoids on the Risk of Tuberculosis Progression

“…Our findings are also consistent with those of a recent study that evaluated role of vitamin A in tuberculosis disease progression among HIV-infected patients. In a cohort of HIV-infected patients from low- and middle-income countries, Tenforde et al [ 31 ] found that VAD, before initiation of antiretroviral therapy, conferred a 5-fold increase in the risk of incident tuberculosis disease.…”

“…Carotenoids are naturally occurring pigments in fruits and vegetables, and 2 studies previously reported decreased tuberculosis risk among children and adult smokers with high intake of fruits and vegetables [ 50 , 51 ]. To our knowledge, only 1 prior study has evaluated the association between carotenoid levels and incident tuberculosis; in that study, baseline total carotenoid levels in HIV-positive patients receiving antiretroviral therapy were not associated with an increased risk of tuberculosis disease [ 31 ].…”

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

“…In a study of Moroccan populations a significantly lower plasma retinol concentration in TB patients compared to healthy controls was observed [147]. In a multinational case-cohort study, it has been reported that both Vitamin A and D deficiencies are associated with the incident of TB cases in HIV-Infected patients, initiating antiretroviral therapy [148]. Zinc deficiency has also been observed in patients with tuberculosis compared to controls [149,150].…”