M. Guidi (1) (2), G. Foletti (3), A. Panchaud (1), P. Tarr (4), B. Sonderegger (5), M. Cavassini (6), A. Telenti (3), M. Rotger (3), C. Csajka (1) (2) and the Swiss HIV Cohort Study
(1) School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva Switzerland; (2) Division of Clinical Pharmacology, Department of Laboratories, University Hospital Lausanne, Lausanne, Switzerland; (3) Institute of Microbiology, University Hospital Lausanne, Lausanne, Switzerland; (4) Medizinische Universitätsklinik, Kantonsspital Bruderholz, Basel, Switzerland; (5) Infectious Diseases Service, Inselspital, Berne, Switzerland; (6) Infectious Diseases Service, University Hospital Lausanne, Lausanne, Switzerland.
Objectives: Vitamin D deficiency is highly prevalent in HIV-infected individuals and has been associated to the progression of the disease and/or to antiretroviral therapy [1,2]. Vitamin D supplementation in patients with plasma levels of 25-hydroxy-vitamine D (25-OHD) < 30 mcg/l has become standard of care. The aim of this analysis was to characterize the time profile of 25-OHD in HIV patients before and after vitamin D supplementation and to test the influence of genetic polymorphisms along with antiretroviral treatment (ART) and non-genetic factors on vitamin D levels. The model served for the simulation of different vitamin D regimens that will help establishing the appropriate dose and time interval for vitamin D supplementation.
Methods: A one-compartment model with first-order absorption and elimination was used to describe 25-OHD concentrations, including a steady-state production rate for the estimation of the endogenous 25-OHD (NONMEM®). Co-administered ART drugs, demographic, environmental variables and seven genetic variants (located on GC, CYP2R1, DHCR7/NADSYN1, CYP24A1) known to influence vitamin D levels according to two genome wide association studies (GWAS) were tested as covariates [3,4].
Results: A total of 1285 25-OHD concentrations, either basal or after a single vitamin D dose supplementation, were collected from 618 patients in three different Swiss hospitals. Average oral clearance was 2.77 L/day, volume of distribution 258 L and endogenous production rate 0.14 micromol/day (CV 39%). Among all the tested covariates, season effect had the most salient impact on vitamin D production rate (maximal increase of 27% (CI95%: 23-30%) at day 228 (220-235 day), i.e. August). Body mass index, smoking status and SNP rs2282679 located on the GC gene, responsible for the vitamin D binding protein transcription, reduced 25-OHD production rate respectively by 39% (CI95%: 24-54 %), 13% (8-19 %) and 20% (7-33 %); while co-administration of darunavir increased it by 16% (5-27 %). An effect of the study center was also observed. The significant covariates explained altogether 12% of the interpatient variability associated to the vitamin D endogenous production rate.
Conclusion: This analysis of 25-OHD plasma levels in HIV infected patients allowed identifying genetic and other risk factors associated with vitamin D deficiency in this population. Improvement of dosage regimen and timing of vitamin D supplementation is proposed based on those results.
References:
[1] Dao, C.N., et al., Low vitamin D among HIV-infected adults: prevalence of and risk factors for low vitamin D Levels in a cohort of HIV-infected adults and comparison to prevalence among adults in the US general population. Clin Infect Dis, 2011. 52(3): p. 396-405.
[2] Van Den Bout-Van Den Beukel, C.J., et al., Vitamin D deficiency among HIV type 1-infected individuals in the Netherlands: effects of antiretroviral therapy. AIDS Res Hum Retroviruses, 2008. 24(11): p. 1375-82.
[3] Ahn, J., et al., Genome-wide association study of circulating vitamin D levels. Hum Mol Genet, 2010. 19(13): p. 2739-45.
[4] Wang, T.J., et al., Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet, 2010. 376(9736): p. 180-8.
Reference: PAGE 22 (2013) Abstr 2873 [www.page-meeting.org/?abstract=2873]
Poster: Infection