France: Factors linked to low vitamin D levels in HIV-positive people

CATIE News

Want to receive publications straight to your inbox?

CATIE

Vitamin D helps the body absorb the minerals calcium and phosphorus, which are used to build bones. Vitamin D also plays a role in maintaining the strength of muscles. Emerging research suggests that vitamin D may also play a role in the health of many organ-systems, including the brain, kidneys, skin and immune system. A diverse range of tissues and cells have receptors that can bind to vitamin D, suggesting that many tissues interact with this vitamin.

Vitamin D and survival

Results from very large observational studies in the United States and Israel suggest that HIV-negative people who have less-than-ideal levels of vitamin D in their blood have an increased risk of dying. Even when adjustments were made for such factors as smoking, diabetes, cholesterol levels, socio-economic status, age, season and so on, Israeli scientists still found that in their study of over 180,000 people, having a vitamin D level in the blood below 50 nanomoles/litre (nmol/l) was significantly associated with an increased risk of dying from a number of different causes.

In another observational study called EuroSIDA, researchers found that vitamin D deficiency was common among HIV-positive people. Several studies in North America and even in relatively sunny Mediterranean countries such as Spain and Italy and tropical countries such as Brazil, Tanzania and Thailand have found vitamin D deficiency to be relatively common among HIV-positive people. The EuroSIDA team found that participants who had less than 12 nanograms/millilitre (ng/ml) of vitamin D in their blood (about 30 nmol/l) were at heightened risk of developing AIDS-related illnesses and dying.

France

French researchers recently completed a study with almost 3,000 HIV-positive people. It will be published in the Journal of Antimicrobial Chemotherapy. In this study, less than ideal levels of vitamin D and vitamin D deficiency were common. What made the French study interesting was that the researchers conducted analyses to find possible factors that might have lowered vitamin D concentrations. One of these possible factors may be a specific anti-HIV therapy. Previous studies have found that exposure to the anti-HIV drug efavirenz (Sustiva, Stocrin and in Atripla) is associated with low vitamin D levels. The present French study confirms this association but also attempts to assess the impact of other commonly used anti-HIV drugs on vitamin D levels.

Study details

Research teams in the following French cities collaborated for this study:

  • Lille
  • Nante
  • Paris
  • Strasbourg
  • Toulouse

Researchers pooled their data collected from 2,994 participants—334 of whom were not taking potent combination anti-HIV therapy (commonly called ART or HAART). People who were being treated for osteoporosis, vitamin D deficiency or kidney failure were not enrolled.

The average profile of participants upon entering the study was as follows:

  • 72% male, 28% female
  • age – 45 years
  • duration of HIV infection – 12 years
  • CD4+ count among ART users – 570 cells
  • CD4+ count among non-ART users – 500 cells
  • 18% were co-infected with hepatitis B or C viruses

Results

Depending on their location and the manufacturer of the vitamin D assay, some researchers assess vitamin D in nanograms/ml while others use nanomoles/l.

The research team defined different vitamin D levels as follows:

  • low levels of vitamin D – any value less than 75 nmol/l (30 ng/ml)
  • insufficient levels of vitamin D – more than 30 nmol/l (12 ng/ml) but less than 75 nmol/l
  • deficient levels of vitamin D – 25 nmol/l (10 ng/ml) or less

Based on these values, the researchers found that 87% of participants had low levels of vitamin D in their blood. This was distributed as follows:

  • insufficient levels of vitamin D – 56%
  • vitamin D deficiency – 31%

Results – Factors associated with vitamin D deficiency

Researchers found that the following factors were linked to having a vitamin D deficiency:

  • smoking tobacco
  • having a CD4+ count less than 350 cells
  • having kidney dysfunction

Impact of ART

Initially researchers found that the use of ART was linked to having low vitamin D levels. However, when further analyses were done to explore this finding among the 2,660 participants who were using ART, they found that deficiency of vitamin D was linked specifically to exposure to the anti-HIV drug efavirenz. The longer a person took efavirenz, the greater the risk of developing vitamin D deficiency

Vitamin D deficiency was not linked to the use of the following drugs:

  • non-nukes – nevirapine (Viramune), etravrine (Intelence)
  • nukes – tenofovir (Viread, and in Truvada, Atripla and Complera), AZT (zidovudine, Retrovir and in Combivir and Trizivir)
  • protease inhibitors – including darunavir (Prezista) and ritonavir (Norvir)
  • integrase inhibitors – raltegravir (Isentress)

This and other studies

The French study is useful because it confirms findings from other studies, namely that the use of efavirenz is associated with reduced levels of vitamin D in the blood. Also, the French study confirms that smoking tobacco is linked to reduced vitamin D levels. This finding is important because smoking among HIV-negative people has been linked to vitamin D deficiency and smoking is also a risk factor for thinner-than-normal bones (osteopenia and osteoporosis).

Another study found that replacing efavirenz with darunavir-ritonavir results in increasing levels of vitamin D. And a randomized study found that participants assigned to receive rilpivirine (Edurant and in Complera) had stable levels of vitamin D while those assigned to receive efavirenz had declining levels of vitamin D.

Why efavirenz?

Laboratory investigation suggests that efavirenz can stimulate the activity of enzymes that degrade vitamin D3 (the active form of this vitamin) and impair the activity of enzymes that convert vitamin D2 to D3.

Study design

The present French study was observational and cross-sectional in nature. It therefore only examined vitamin D levels at one point in time. Moreover, researchers were not able to take into account factors that could have biased their conclusions, such as sun exposure, skin colour and ethnicity. These limitations all mean that this study’s conclusions need to be interpreted with care. However, the findings from the French study on the impact of efavirenz on vitamin D levels were similar to those of several other studies, including randomized clinical trials. Moreover, the French study was relatively large, something that strengthens its conclusions.

This and other studies underscore the need to assess vitamin D levels in HIV-positive people. If insufficiency or deficiency is detected, there are guidelines for supplementation that have been produced by hormone specialists. Such supplementation should always be done under medical supervision. For more information about the vitamin D guidelines and vitamin D in general, please see TreatmentUpdate 185.

                                                                                                                                                            —Sean R. Hosein

REFERENCES:

  1. Anderson JL, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. American Journal of Cardiology. 2010 Oct 1;106(7):963-8.
  2. Saliba W, Barnett O, Rennert HS, et al. The risk of all-cause mortality is inversely related to serum 25(OH)D levels. Journal of Clinical Endocrinology and Metabolism. 2012; in press.
  3. Walker Harris V, Brown TT. Bone loss in the HIV-infected patient: Evidence, clinical implications, and treatment strategies. Journal of Infectious Diseases. 2012 Jun;205 Suppl 3:S391-8.
  4. Allavena C, Delpierre C, Cuzin L, Rey D, Viget N, Bernard J, Guillot P, Duvivier C, Billaud E, Raffi F. High frequency of vitamin D deficiency in HIV-infected patients: effects of HIV-related factors and antiretroviral drugs. Journal of Antimicrobial Chemotherapy. 2012; in press.
  5. Chotalia J, Frontini M, Tatini P, Nsuami MJ, Martin DH, Clark RA. Vitamin D deficiency in HIV-infected and -uninfected women in the United States. Journal of Acquired Immune Deficiency Syndromes. 2012 Apr 1;59(4):e77.
  6. Khoo AL, Chai L, Koenen H, Joosten I, Netea M, van der Ven A. Translating the role of vitamin D3 in infectious diseases. Critical Reviews in Microbiology. 2012 May;38(2):122-35.
  7. Conrado T, Miranda-Filho Dde B, Ximenes RA, et al. Vitamin D deficiency in HIV-infected women on antiretroviral therapy living in the tropics. Journal of the International Association of Physicians in AIDS Care. 2011 Jul-Aug;10(4):239-45.
  8. Wiboonchutikul S, Sungkanuparph S, Kiertiburanakul S, Chailurkit LO, Charoenyingwattana A, Wangsomboonsiri W, Chantratita W, Ongphiphadhanakul B. Vitamin D insufficiency and deficiency among HIV-1-Infected patients in a tropical setting. Journal of the International Association of Physicians in AIDS Care. 2012; in press.
  9. Cervero M, Agud JL, García-Lacalle C, Alcázar V, Torres R, Jusdado JJ, Moreno Guillén S. Prevalence of Vitamin D deficiency and its related risk factor in a Spanish cohort of adult HIV-infected patients: affects of antiretroviral therapy. AIDS Research & Human Retroviruses. 2012; in press.
  10. Kwan CK, Eckhardt B, Baghdadi J, Aberg JA. Hyperparathyroidism and complications associated with vitamin D deficiency in HIV-infected adults in New York City, New York. AIDS Research & Human Retroviruses. 2012; in press.
  11. Estrella MM, Kirk GD, Mehta SH, Brown TT, Fine DM, Atta MG, Lucas GM. Vitamin D deficiency and persistent proteinuria among HIV-infected and uninfected injection drug users. AIDS. 2012 Jan 28;26(3):295-302.
  12. Brown TT, McComsey GA. Association between initiation of antiretroviral therapy with efavirenz and decreases in 25-hydroxyvitamin D. Antiviral Therapy. 2010;15(3):425-9.
  13. Childs K, Welz T, Samarawickrama A, Post FA. Effects of vitamin D deficiency and combination antiretroviral therapy on bone in HIV-positive patients. AIDS. 2012 Jan 28;26(3):253-62.
  14. Dao CN, Patel P, Overton ET, 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. Clinical Infectious Diseases. 2011 Feb 1;52(3):396-405.
  15. Fox J, Peters B, Prakash M, et al. Improvement in vitamin D deficiency following antiretroviral regime change: Results from the MONET trial. AIDS Research & Human Retroviruses. 2011 Jan;27(1):29-34.
  16. Viard JP, Souberbielle JC, Kirk O, et al. Vitamin D and clinical disease progression in HIV infection: results from the EuroSIDA study. AIDS. 2011 Jun 19;25(10):1305-15.
  17. Fabbriciani G, De Socio GV. Efavirenz and bone health. AIDS. 2009 Jun 1;23(9):1181.