Vitamin D deficiency in HIV-infected patients: associated with non-nucleoside reverse transcriptase inhibitor or efavirenz use?

We read with interest recent articles by Mueller et al.[1] and Welz et al.[2] on the prevalence and factors associated with vitamin D deficiency in HIV-infected patients. As far as exposure to specific antiretroviral drugs are considered, Mueller et al.[1] demonstrated that non-nucleoside reverse transcriptase inhibitor (NNRTI) use is associated with 25-hydroxy-vitamin D [25(OH)D] deficiency. Welz et al.[2] demonstrated that the current use of efavirenz but not nevirapine is associated with severe 25(OH)D deficiency. Although the number of studies stating that NNRTI use is associated with vitamin D deficiency is growing it is unclear whether this association is related to NNRTI class or to efavirenz use [3,4]. We assessed factors associated with vitamin D deficiency in HIV-infected patients in our Tourcoing Clinical Cohort [5] in Northern France and more specifically studied the impact of NNRTI use on 25(OH)D level. HIV-infected patients included in this study were those followed by three physicians of the clinic in whom 25(OH)D serum levels were prospectively evaluated from 1 December 2008 to 1 April 2009. Vitamin D deficiency was defined by a level of 25(OH)D below 30 nmol/l. We used univariate linear regression models to evaluate the correlation between patients characteristics and 25(OH)D levels. Moreover, a multivariate linear regression model was used to assess the correlation between NNRTI and 25(OH)D levels adjusted on variables associated with 25(OH)D level at a P value 0.20 or less in the univariate analysis. Overall, 395 patients were included. The median age was 45 years [interquartile range (IQR) 40–52], 68% were men, 14% were from sub-Saharan Africa, the median body mass index (BMI) was 24 (IQR 21–26), 10% were hepatitis C-positive and the median CD4 cell count was 575/μl (IQR 430–757). Three hundred and fifty-two patients (89%) were on combination antiretroviral therapy (cART) of whom 88% had a viral load less than 50 copies/ml. Among those receiving cART, 125 (35%) had an NNRTI-containing regimen of whom 58 (46.4%) on efavirenz and 58 on nevirapine (46.4%); 231 (66%) were on a protease inhibitor-containing regimen; and 117 (33%) were receiving tenofovir. The median 25(OH)D level was 38 nmol/l (IQR 20–52), and 160 patients (41%) had a 25(OH)D deficiency. In the univariate analysis, current exposure to NNRTI tend to be correlated with vitamin D deficiency (P = 0.06) (model 1; Table 1), but not current exposure to efavirenz (P = 0.17) or nevirapine (P = 0.20) (model 2; Table 1). However, the crude coefficient estimate for NNRTI in the linear regression model (−5.66) was close to the coefficient estimate for efavirenz (−5.30) and nevirapine (−5.04) (Table 1) in a second model with four classes (efavirenz use, nevirapine use, etravirine use versus no NNRTI use). There was a trend toward a correlation between time under tenofovir and vitamin D deficiency (P = 0.09). In the multivariate analysis, when adjusted on factors associated with 25(OH)D level in the univariate analysis, current exposure to NNRTI remained significantly correlated (coefficient = −5.94, P = 0,05) with vitamin D deficiency in a first model but not efavirenz and nevirapine in a second model. However, coefficient estimates for NNRTIs and efavirenz or nevirapine were again comparable.Table 1: Factors associated with vitamin D deficiency in 352 HIV-infected patients on combination antiretroviral therapy (1 December 2008 to 1 April 2009; Tourcoing clinical cohort, France).In this study, performed in winter/spring season, likewise in other studies, severe vitamin D deficiency was found to be highly prevalent [3,6]. NNRTI current use was associated with lower levels of 25(OH)D as described by Mueller et al. [1] but not efavirenz and nevirapine use. However, the lack of correlation between efavirenz and nevaripine use and 25(OH)D level in our study is probably related to the lack of the statistical power of our analysis. Comparable coefficient estimates of efavirenz, nevirapine, and NNRTIs in linear regression models are in favour of the NNRTI class impact on vitamin D deficiency and not only efavirenz. It has been postulated that this correlation is related to an increased catabolism of 25(OH)D through induction of CYP450, CYPA4, CYP24, and CYP 2C9 [7,8]. Both efavirenz and nevirapine have been described as acting on those cytochromes [7,8]; thus, if this is the only underlying mechanism of vitamin deficiency, it is not understood why only efavirenz and not NNRTI class is associated with vitamin deficiency.