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AIDS:
doi: 10.1097/QAD.0b013e3283454461
Correspondence

Do nevirapine and efavirenz affect vitamin D homeostasis similarly?

Welz, Tanyaa; Childs, Katea; Post, Frank Aa,b

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aDepartment of HIV Medicine and Sexual Health, King's College Hospital, UK

bKing's College London School of Medicine, London, UK.

Received 14 January, 2011

Accepted 1 February, 2011

Correspondence to Dr Frank A. Post, King's College London School of Medicine at Guy's, King's College, and St Thomas' Hospitals, Weston Education Ctenter, Cutcombe Road, London SE5 9RJ, UK. Tel: +44 2078485779; fax: +44 2078485769; e-mail: frank.post@kcl.ac.uk

Pasquet and colleagues observed, in keeping with previous studies [1–5], an association between exposure to non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing antiretroviral therapy and vitamin D deficiency in their cross-sectional cohort study [6]. Their study was insufficiently powered to look at individual NNRTI, and no significant association between vitamin D deficiency and either efavirenz or nevirapine was observed. However, comparable crude and adjusted coefficients for efavirenz and nevirapine led the authors to question whether the observed association between vitamin D deficiency and NNRTI reflects an NNRTI class effect rather than a phenomenon restricted to efavirenz as reported by ourselves [2].

An increasing body of evidence supports an association between efavirenz and 25-hydroxy-vitamin D [25(OH)D] deficiency [2,7,8]. Initiation of efavirenz appears to be consistently associated with reductions in 25(OH)D levels [5,6,9], and preliminary data suggest that etravirine and efavirenz may have similar effects on 25(OH)D homeostasis [10]. Although we found an association between efavirenz use and severe 25(OH)D deficiency [adjusted odds ratio (aOR) 2.0 (1.5, 2.7)] as well as raised alkaline phosphatase levels [aOR 1.6 (1.02, 2.4)], nevirapine use appeared to be protective against 25(OH)D deficiency [aOR 0.6 (0.3, 1.5)] and raised alkaline phosphatase [aOR 0.5 (0.3, 0.9)] in multivariate models adjusted for sex, ethnicity, season and CD4 cell count [2], and no association between nevirapine and 25(OH)D deficiency or insufficiency was observed in the SUN cohort [7]. Whilst comparable reductions in 25(OH)D have been observed in patients initiating efavirenz and nevirapine [5], the small sample size of this study precluded inclusion of individual NNRTI in multivariate analyses. Furthermore, no significant reductions in 25(OH)D from baseline were observed in 18 patients who initiated zidovudine, lamivudine and nevirapine [11] and in 27 patients who commenced nevirapine together with ritonavir-boosted lopinavir [12]. Whereas the effects of antiretroviral treatment-associated reductions in 25(OH)D on bone remain to be defined, a trend toward lower bone mineral density (BMD) with efavirenz and higher BMD with nevirapine has been reported in HIV infected children [13].

In clinical practice, efavirenz and nevirapine are preferentially used in some patients and avoided in others; associations with either NNRTI in observational cohort studies may thus be subject to channelling bias. For example, nevirapine may be the drug of choice for premenopausal African women with low CD4 cell counts and efavirenz for white men with preserved CD4 cell counts. As black ethnicity, female sex and low nadir CD4 cell count were all independently associated with severe vitamin D deficiency in our study [2], an inability to adjust for these factors may lead to a spurious association between nevirapine and vitamin D deficiency in cross-sectional studies. On the contrary, 61% of our patients were black, and it is possible that the effects of nevirapine on 25(OH)D homeostasis differ by ethnicity [14]. Of note, the two studies that reported a decline in 25(OH)D with nevirapine or an association between nevirapine and vitamin D deficiency predominantly included white men with preserved CD4 cell counts, did not adjust for sex, ethnicity and nadir CD4 cell count, and showed that 25(OH)D levels in black patients were minimally affected by antiretroviral treatment [5,6].

The consistent finding that vitamin D deficiency is very common in HIV-infected patients raises more important questions than which antiretroviral drug(s) may be implicated, namely what is the clinical significance of low 25(OH)D and is there any benefit from vitamin D supplementation? Vitamin D deficiency in the general population has been associated with numerous adverse health outcomes including cardiovascular disease, cancer, infection, osteopenia and fractures [15]. HIV infection is associated with an increased risk of (opportunistic) infections, cancer [16] and low BMD [17], and exposure to antiretroviral therapy with an increased risk of cardiovascular events [18] and further reductions in BMD [19]. As the greatest reductions in BMD are observed in patients who initiate antiretroviral therapy [12,20–21], the contribution of vitamin D deficiency and the potential of vitamin D supplementation to reduce this initial bone loss deserve further study. An effect of ethnicity and specific antiretrovirals, especially efavirenz and tenofovir, should be considered in the design of these studies.

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Acknowledgements

None of the authors has any financial or personal relationships with people or organizations that could inappropriately influence this work, although all authors have, at some stage in the past, received funding from a variety of pharmaceutical companies for travel grants. In addition, F.A.P. has received research funding, speaking engagements or consultancy fees from GlaxoSmithKline, ViiV, Tibotec, Bristol-Meyers Squibb and Gilead Sciences.

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References

1. Mueller NJ, Fux CA, Ledergerber B, Elzi L, Schmid P, Dang T, et al. High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients. AIDS 2010; 24:1127–1134.

2. Welz T, Childs K, Ibrahim F, Poulton M, Taylor CB, Moniz CF, et al. Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase. AIDS 2010; 24:1923–1928.

3. Rodriguez M, Daniels B, Gunawardene S, Robbins GK. High frequency of vitamin D deficiency in ambulatory HIV-Positive patients. AIDS Res Hum Retroviruses 2009; 25:9–14.

4. Rosenvinge MM, Gedela K, Copas AJ, Wilkinson A, Sheehy CA, Bano G, et al. Tenofovir-linked hyperparathyroidism is independently associated with the presence of vitamin D deficiency. J Acquir Immune Defic Syndr 2010; 54:496–499.

5. Conesa-Botella A, Florence E, Lynen L, Colebunders R, Menten J, Moreno-Reyes R. Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen. AIDS Res Ther 2010; 7:40.

6. Pasquet A, Viget N, Ajana F, de la Tribonniere X, Dubus S, Paccou J, et al. Vitamin D deficiency in HIV infected patients: associated with NNRTI or efavirenz use? AIDS 2011; 25:873–874.

7. Dao CN, Patel P, Overton ET, Rhame F, Pals SL, Johnson C, et al. Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN) Investigators. 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; 52:396–405.

8. Fox J, Peters B, Prakash M, Arribas J, Hill A, Moecklinghoff C. Improvement in vitamin D deficiency following antiretroviral regime change: results from the MONET Trial. AIDS Res Hum Retroviruses 2011; 27:29–34.

9. Brown TT, McComsey GA. Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D. Antivir Ther 2010; 15:425–429.

10. Rockstroh J, Stoehr A, Duiculescu D, et al. Analysis of Vitamin D and parathyroid hormone in the SENSE trial: etravirine versus efavirenz in treatment-naïve HIV-1 infected patients. Antivir Ther 2010; 15(S4):A42.

11. Lattuada E, Lanzafame M, Zoppini G, Concia E, Vento S. No influence of nevirapine on vitamin D deficiency in HIV-infected patients. AIDS Res Hum Retroviruses 2009; 25:849–850.

12. van Vonderen MG, Lips P, van Agtmael MA, Hassink EA, Brinkman K, Geerlings SE, et al. First line zidovudine/lamivudine/lopinavir/ritonavir leads to greater bone loss compared to nevirapine/lopinavir/ritonavir. AIDS 2009; 23:1367–1376.

13. Jacobson DL, Spiegelman D, Duggan C, Weinberg GA, Bechard L, Furuta L, et al. Predictors of bone mineral density in human immunodeficiency virus-1 infected children. J Pediatr Gastroenterol Nutr 2005; 41:339–346.

14. Mahungu T, Smith C, Turner F, Egan D, Youle M, Johnson M, et al. Cytochrome P450 2B6 516G–>T is associated with plasma concentrations of nevirapine at both 200 mg twice daily and 400 mg once daily in an ethnically diverse population. HIV Med 2009; 10:310–317.

15. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357:266–281.

16. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 2007; 370:59–67.

17. Brown TT, Qaqish RB. Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 2006; 20:2165–2174.

18. Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte A, El-Sadr W, et al. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med 2007; 356:1723–1735.

19. Grund B, Peng G, Gibert CL, Hoy JF, Isaksson RL, Shlay JC, et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS 2009; 23:1519–1529.

20. Stellbrink HJ, Orkin C, Arribas JR, Compston J, Gerstoft J, Van Wijngaerden E, et al. Comparison of changes in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults: 48-week results from the ASSERT study. Clin Infect Dis 2010; 51:963–972.

21. Brown TT, McComsey GA, King MS, Qaqish RB, Bernstein BM, da Silva BA. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 2009; 51:554–561.

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