{"id":10248,"date":"2010-04-02T12:40:08","date_gmt":"2010-04-02T12:40:08","guid":{"rendered":"http:\/\/i-base.info\/htb\/?p=10248"},"modified":"2013-08-07T09:17:53","modified_gmt":"2013-08-07T09:17:53","slug":"10248","status":"publish","type":"post","link":"https:\/\/i-base.info\/htb\/10248","title":{"rendered":"Vitamin D deficiencies in HIV management"},"content":{"rendered":"

Nathan Geffen, TAC<\/strong><\/p>\n

HTB has run several articles on vitamin D deficiencies in previous issues in relation to bone problems, tenofovir and efavirenz. <\/strong><\/p>\n

There is increasing\u00a0concern and research about vitamin D deficiency in people with HIV, especially with regard to African immigrants and people of African descent living in\u00a0the cold climates of North America and Europe.<\/p>\n

There were several posters on this topic at CROI 2010 and so a themed discussion on it was held, chaired by\u00a0discussants Peter Reiss of the University of Amsterdam and Michael Yin of Columbia University. Reiss started the session by giving a clear explanation of\u00a0the basic science of vitamin D. [1-3]<\/p>\n

Background<\/strong><\/h2>\n

Vitamin D is a group of fat soluble prohormones that mainly originate in the\u00a0skin where ultraviolet radiation interacts with 7-dehydrocholesterol to form pre-vitamin D3 and then vitamin D3. This process is harder in people with\u00a0darker skins. Some vitamin D3 is also consumed from diet and supplements. The main purpose of vitamin D is to increase the flow of calcium in the\u00a0bloodstream.<\/p>\n

Vitamin D3 is hydroxylated by the enzyme 25-hydroxylase into hydroxylated vitamin D, 25(OH)D, in the liver.\u00a0 An alternative pathway to hydroxylated
\nvitamin D is via vitamin D2 acquired from diet, but this is considered a less important source.<\/p>\n

The hydroxylated vitamin D, 25(OH)D is then further hydroxylated in the kidneys to one-alpha-hydroxylated-vitamin D (1a-25(OH)2D) which is the active\u00a0metabolite. The enzymes involved in this process belong to the cytochrome p450 family, which is a catalyst for some antiretrovirals. There is also\u00a0speculation that HIV itself affects the production of vitamin D (discussed further below).<\/p>\n

Even though 1a-25(OH)2D is the active metabolite, for diagnostic purposes the amount of its precursor, 25(OH)D is\u00a0 measured. This is because if there is a\u00a0deficiency in 25(OH)D, an auto-regulatory mechanism upregulates the manufacture of 1a-25(OH)2D. So a person can have sufficient amount of the active\u00a0metabolite, but still have a deficiency of vitamin D.<\/p>\n

Clinical consequences of vitamin D deficiency<\/strong><\/h2>\n

Widely accepted criteria for\u00a0clinically sufficient, insufficient and deficient levels of vitamin D are given in Table 1. However, as Reiss pointed out, by this definition, 40 to 100%\u00a0of elderly people are deficient in vitamin D and the criteria do not account for ethnic differences. Moreover optimum levels of vitamin D for skeletal and\u00a0extra-skeletal health have not been established neither in the general population nor for specific ethnic groups.\u00a0 As is clear from the presentations\u00a0described in Table 1 below, these criteria are not standardised.<\/p>\n

Julian Falutz of McGill University has compiled a table of studies examining vitamin D levels in people with HIV (Table 2). They cover a wide range of\u00a0countries, seasons, CD4 count ranges and levels of ARV uptake, giving a diverse range of proportions of people categorised as sufficient, insufficient or\u00a0deficient.<\/p>\n

Table 1: Criteria for clinical definitions of 25(OH)D3 in blood (Reiss [3])<\/strong><\/p>\n\n\n\n\n\n\n
<\/td>\nEuropean (SI)
\nmeasurement (nanomoles\/L)<\/td>\n		US measurement (nanograms\/mL)<\/td>\n<\/tr>\n
Sufficient<\/td>\n>=75 nmol\/L<\/td>\n>=30 ng\/mL<\/td>\n<\/tr>\n
Insufficient<\/td>\n0\u009675 nmol\/L<\/td>\n20-30 ng\/mL<\/td>\n<\/tr>\n
Deficient<\/td>\n<50 nmol\/L<\/td>\n<20 ng\/mL<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

Table 2: Vitamin D studies in people with HIV (Falutz)<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n
Study<\/td>\nN<\/td>\nSex\/race<\/td>\nAge<\/td>\nCD4<\/td>\nARV (%)<\/td>\nSeason<\/td>\n25(OH)D Low (%)<\/td>\n25(OH)D Insufficient (%)<\/td>\n25(OH)D Normal (%)<\/td>\n<\/tr>\n
Stephensen (US) 2000<\/td>\n238(+) 121(-)<\/td>\n72%F, 75%B<\/td>\n20<\/td>\n?<\/td>\n?<\/td>\n86% Spring-Summer<\/td>\n?<\/td>\n87<\/td>\n?<\/td>\n<\/tr>\n
Seminari (Italy) 2002<\/td>\n68<\/td>\n80%M, all W<\/td>\n41<\/td>\n150<\/td>\n100<\/td>\nNov-Jun<\/td>\n?<\/td>\n81<\/td>\n?<\/td>\n<\/tr>\n
Bang (Sweden) 2004<\/td>\n115<\/td>\nM, all white<\/td>\n44<\/td>\n480<\/td>\n62<\/td>\nAutumn-Winter<\/td>\n23<\/td>\n36<\/td>\n40<\/td>\n<\/tr>\n
Rubin (NYC) 2005<\/td>\n62<\/td>\nM, 34% white<\/td>\n48<\/td>\n540<\/td>\n92<\/td>\nAutumn-Winter<\/td>\n42<\/td>\n34<\/td>\n24<\/td>\n<\/tr>\n
Rodriguez (Boston) 2005<\/td>\n57<\/td>\n77% M, 60% W<\/td>\n46<\/td>\n430<\/td>\n81<\/td>\nWinter-Spring<\/td>\n48<\/td>\n?<\/td>\n?<\/td>\n<\/tr>\n
V. der Ven (Holland) 2006<\/td>\n254<\/td>\n75% M, 73% W<\/td>\n41<\/td>\n420<\/td>\n79<\/td>\nJan-Aug<\/td>\n29<\/td>\n?<\/td>\n71<\/td>\n<\/tr>\n
Wetz (London) 2008<\/td>\n47<\/td>\n60% M, 60% B<\/td>\n41<\/td>\n455<\/td>\n88<\/td>\n30% Autumn-Winter<\/td>\n74<\/td>\n17<\/td>\n9<\/td>\n<\/tr>\n
Garcia-Aperico (Spain) 2008<\/td>\n30<\/td>\n100% M and W<\/td>\n38<\/td>\n550<\/td>\n56<\/td>\nOct-Jun<\/td>\n86<\/td>\n?<\/td>\n?<\/td>\n<\/tr>\n
Falutz<\/td>\n41<\/td>\n83% M<\/td>\n54<\/td>\n549<\/td>\n100<\/td>\nAutumn<\/td>\n5<\/td>\n55<\/td>\n40<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

The role of HIV and its treatment in vitamin D regulation is speculative and complex. HIV might affect\u00a0dietary intake in sick people which in turn might affect levels of vitamin D. HIV might also affect the 1-alpha hydroxylation step and thereby inhibit\u00a0synthesis of the active metabolite. Vitamin D might also be used by maturing and proliferating T-cells. With their increased production during HIV\u00a0infection, there might be greater utilisation of vitamin D. The utilisation of cytochrome p450 enzymes by NNRTIs and protease inhibitors might also affect\u00a0levels of vitamin D.\u00a0 The hydroxylation step in the kidney takes place in the proximal tubular cells, which are also affected by tenofovir, and this might\u00a0impact on vitamin D levels. On the other hand ritonavir inhibits 1a-hydroxylase and consequently this might lead to an accumulation of unconverted 25(OH)D\u00a0in the kidneys.<\/p>\n

Vitamin D receptors are found on nearly all cells and deficiency of it is associated with many diseases such as osteomalacia (softening of bones),\u00a0inflammatory conditions, hypertension, cardiovascular disease, insulin resistance, renal disease, prostate and colon cancer, greater risk of bacterial\u00a0infection, cognitive dysfunction and frailty.<\/p>\n

The SUN study<\/strong><\/h2>\n

Christine Dao of the CDC presented results of the SUN study. This\u00a0study assessed levels of vitamin D (measured by 25(OH)D, as with all other studies presented here) from 2004 to 2006 in the United States in 672 adults\u00a0with HIV. Insufficiency was defined as less than 30 ng\/mL. The study found 72% of participants were vitamin D insufficient. Black race, Hispanic ethnicity,\u00a0lower ultraviolet exposure, hypertension, lack of exercise and efavirenz exposure were independently associated with insufficiency. On the other hand\u00a0renal insufficiency (GFR<90) and ritonavir exposure were independently associated with lower odds of insufficiency. In question time, Dao stated that\u00a09% of participants were deficient, defined in this study as a 25(OH)D less than 10 ng\/mL (which is different from the definition of deficiency given\u00a0above). [4]<\/p>\n

Italian cohort<\/h2>\n

Antonella d\u0092 Arminio Monforte from the University of Milan presented the results of an observational cohort with\u00a0retrospective analysis in vitamin D in stored plasma samples of 852 patients contributing 1,498 measurements. Of these, 262 measurements were taken before\u00a0and 1,236 after ART initiation. Insufficiency was defined the same way as the European measurement in Table 1, but deficiency was defined as less than 30\u00a0nmol\/L. [5]<\/p>\n

Insufficiency was found in 804 measurements (54%), while deficiency was found in 98 (7%). In 116 patients measured pre- and post-ART initiation in the\u00a0same season, there was a non-significant drop of vitamin D levels (average of 7.57 nmol\/L per year; p=0.11).<\/p>\n

The following were significantly associated with deficiency versus normal values (adjusted odds ratios):<\/p>\n