Daily Nutritional Supplementation with Vitamin D₃ and Phenylbutyrate to Treatment-Naïve HIV Patients Tested in a Randomized Placebo-Controlled Trial

Abstract

Poor nutritional status is common among human immunodeficiency virus (HIV)-infected patients including vitamin D (vitD₃) deficiency. We conducted a double-blinded, randomized, and placebo-controlled trial in Addis Ababa, Ethiopia, to investigate if daily nutritional supplementation with vitD₃ (5000 IU) and phenylbutyrate (PBA, 2 × 500 mg) could mediate beneficial effects in treatment-naïve HIV patients. Primary endpoint: the change in plasma HIV-1 comparing week 0 to 16 using modified intention-to-treat (mITT, n = 197) and per-protocol (n = 173) analyses. Secondary endpoints: longitudinal HIV viral load, T cell counts, body mass index (BMI), middle-upper-arm circumference (MUAC), and 25(OH)D₃ levels in plasma. Baseline characteristics were detectable viral loads (median 7897 copies/mL), low CD4⁺ (median 410 cells/µL), and elevated CD8⁺ (median 930 cells/µL) T cell counts. Most subjects were vitD₃ deficient at enrolment, but a gradual and significant improvement of vitD₃ status was demonstrated in the vitD₃ + PBA group compared with placebo (p < 0.0001) from week 0 to 16 (median 37.5 versus 115.5 nmol/L). No significant changes in HIV viral load, CD4⁺ or CD8⁺ T cell counts, BMI or MUAC could be detected. Clinical adverse events were similar in both groups. Daily vitD₃ + PBA for 16 weeks was well-tolerated and effectively improved vitD₃ status but did not reduce viral load, restore peripheral T cell counts or improve BMI or MUAC in HIV patients with slow progressive disease. Clinicaltrials.gov NCT01702974.

Keywords: HIV infection; clinical trial; immunity; nutrition; supplementation; vitamin D.

Figure 1

Trial profile. Flow diagram of patients screened for human immunodeficiency virus (HIV) infection. Patients ineligible for randomization included age <18 years (n = 27), pregnancy or breast feeding (n = 40), home parenteral nutrition (n = 56), low HIV viral loads <1000 copies/mL (n = 60), low CD4⁺ T cell counts <350 cells/µL (n = 16), initiated antiretroviral therapy (ART; n = 1), liver diseases (n = 2), shortage of study medication (n = 2) and patients who declined to participate (n = 80). Delayed laboratory results that were received after randomization confirmed that some patients had low HIV viral loads <1000 copies/mL (n = 78), liver disease (n = 1), and low CD4⁺ T cells counts <200 cells/µL (n = 2). Discontinued intervention included patients who initiated ART (n = 8), pregnancy (n = 3), tuberculosis infection (n = 2), and adverse events (n = 1). Patients who dropped out from the study included patients who withdrew their consent (=6), moved from the study area (n = 3), or could not be reached (n = 1).

Figure 2

Primary efficacy analyses. HIV viral load was assessed at baseline and at weeks 4, 8, 16, and 24 after initiation of vitD₃ + PBA supplementation. The efficacy analysis included comparison of log HIV viral load in the vitD₃ + PBA and placebo treatment groups between week 0 and week 8. Crude data from the mITT cohort are presented as the mean and 95% CI. The solid line represents placebo while the dotted line represents vitD₃ + PBA treatment.

Figure 3

Secondary analyses. Peripheral CD4⁺ and CD8⁺ T cell counts, BMI, and MUAC were assessed at baseline and at weeks 4, 8, 16, and 24 after initiation of vitD₃ + PBA supplementation. (a) CD4⁺ T cell counts, (b) CD8⁺ T cell counts, (c) BMI, (d) MUAC. Crude data from the mITT cohort are presented as the median and 95% CI. In a–d, the solid line represents placebo while the dotted line represents vitD₃ + PBA treatment. BMI, Body Mass Index; MUAC, Mid-Upper-Arm Circumference.

Figure 4

Vitamin D status. Plasma levels of 25(OH)D₃ were assessed at baseline and at weeks 4, 8, and 16 after initiation of vitD₃ + PBA supplementation. Placebo (circles) compared with the vitD₃ + PBA group (triangles) is shown in a scatter dot plot. The solid line indicates the median, and the dashed lines mark the different thresholds for vitD₃ deficiency and insufficiency [13].