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Efavirenz and bone health
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"Anticonvulsant medication and other cytochrome P450 inducers, including rifabutin and rifampicin, are associated with osteomalacia due to induction of hepatic metabolism"...."We propose that the vitamin D deficiency was caused by increased hepatic turnover due to CYP450 enzyme induction by efavirenz"
AIDS:
1 June 2009 - Volume 23 - Issue 9 - p 1181
Correspondance
Fabbriciani, Gianluigi; De Socio, Giuseppe Vittorio L
aUnit of Internal Medicine, Angiology and Arteriosclerosis Diseases, University of Perugia, Italy
bUnit of Infectious Diseases, Hospital Santa Maria della Misericordia Perugia, Italy.
Correspondence to Dr Gianluigi Fabbriciani, MD, Institute of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Clinical and Experimental Medicine, University of Perugia, Piazzale Menghini, 1, IT-06129 Perugia, Italy. Tel: +39 075 5784028; fax: +39 075 5784022; e-mail: glfabbriciani@tiscali.it
Herzmann and Arasteh [1] reported the case of an HIV-infected 45-year-old white woman under treatment with efavirenz, lamivudine and abacavir, who was admitted for a 3-month history of generalized bone pain, severe proximal myopathy and metatarsal and multiple rib fractures. A diagnosis of osteomalacia from deficiency of vitamin D was made and it was attributed to abnormal vitamin D metabolism secondary to efavirenz use. The article remarks that surprisingly, the addition of vitamin D3 and calcium to the antiretroviral therapy did not have a result as the normalization of mineral and bone metabolism, whereas the eventual stoppage of efavirenz resulted in 3 months into remission of osteomalacia under both clinical and laboratory viewpoints.
The authors reported an interesting case and it has to be agreed with them that a supplementation of calcium and vitamin D should be adopted in patients undergoing treatment with efavirenz. However, it would have been desirable to find in this case report important information such as details about duration and dose of the vitamin D3 and calcium therapy adopted.
Efavirenz may accelerate catabolism of vitamin D through the upregulation of 25-hydroxyvitamin D3-24-hydroxylase (CYP24) gene expression [2,3]. It is well known that some antiepileptic drugs (AEDs) (e.g. phenobarbital, phenytoin, etc.) [4] can induce enzymes such as efavirenz and hepatic cytochrome P450, so they may be associated with hypovitaminosis D. Therefore, patients on long-term treatment with AEDs are at a greater risk of osteopenia/osteoporosis, osteomalacia and fractures [5], which can be reduced following specific prophylaxis. It seems to us that, the same preventive and therapeutic measures followed for the management of AEDs-induced bone diseases could and should be adopted in patients treated with efavirenz. Patients, who have increase degradation of vitamin D secondary to AEDs or efavirenz, need higher daily doses of vitamin D to maintain normal levels. Thus, disturbances in calcium homeostasis can be prevented by vitamin D3 supplementation at doses of up to 2000 IU/day in patients under antiepileptic treatment [6] as well as in those who are started on treatment with efavirenz. For individuals with documented vitamin D deficiency, treatment with 50 000 IU/week for 8 weeks has been recommended and can be repeated if vitamin D levels remain low after initial treatment [7]. This may be followed by supplementation with vitamin D3 2000 IU once a day to maintain the levels above the threshold of insufficiency. Calcium supplementation with doses of 1-1.5 mg/day should be prescribed to all persons using efavirenz such as patients using AEDs [7], particularly in presence of multiple risk factors for osteoporosis or documented low bone mineral density.
In our opinion, an adequate vitamin D and calcium supplementation can easily prevent efavirenz-induced osteomalacia without renouncing to an important first-line drug in the management of HIV infection.
References
1. Herzmann C, Arasteh K. Efavirenz-induced osteomalacia. AIDS 2009; 23:274-275.
2. Gyllensten K, Josephson F, Lidman K, Saaf M. Severe vitamin D deficiency diagnosed after introduction of antiretroviral therapy including efavirenz in a patient living at latitude 59 degrees N. AIDS 2006; 20:1906-1907.
3. Barrett JS, Joshi AS, Chai M, Ludden TM, Fiske WD, Pieniaszek HJ Jr. Population pharmacokinetic meta-analysis with efavirenz. Int J Clin Pharmacol Ther 2002; 40:507-519.
4. Hahn TJ, Hendin BA, Scharp CR, Haddad JG. Effects of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972; 287:900-904.
5. Khanna S, Pillai KK, Vohora D. Insights into liaison between antiepileptic drugs and bone. Drug Discov Today 2009; 14:428-435.
6. Petty SJ, O'Brien TJ, Wark JD. Antiepileptic medication and bone health. Osteop Int 2007; 18:129-142.
7. Valsamis HA, Arora SK, Labban B, McFarlane SI. Antiepileptic drugs and bone metabolism. Nutr Metab (Lond) 2006; 3:36.
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