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CROI 2010: Vitamin D Deficiency is Widespread among People with HIV in U.S., Europe, and Africa

Low levels of vitamin D are common among HIV positive people around the world, especially in seasons when people get less sun exposure, according to a series of studies presented at the 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010) last month in San Francisco. Vitamin D deficiency promotes bone loss and has been linked to conditions including cardiovascular disease, cancer, and vaginal inflammation.

Vitamin D is a fat-soluble compound that plays an important role in metabolism. It is manufactured by the body when exposed to UV light from the sun, and is also available in foods including cold-water fish and fortified milk. Individuals with darker skin produce less vitamin D from sunlight, people have lower levels during seasons with shorter days, and covering the skin with clothing or sunscreen inhibits its production.

Vitamin D's active form, calcitriol or 1,25-dihydroxyvitamin, acts as a steroid hormone that regulates bone composition by increasing absorption of calcium and maintaining a balance between cells that build bone (osteoblasts) and others that break it down (osteoclasts). Bone loss is a concern for people with HIV, who are at higher risk for reasons that are not fully understood but may be related to antiretroviral drugs or systemic inflammation.

Calcidiol or 25-hydroxyvitamin D is the form typically measured in the blood when testing for deficiency. Levels above 30 ng/mL are considered sufficient, 20-30 ng/mL is considered insufficient, and levels below 20 ng/mL are considered deficient.

U.S. Studies

The CROI poster discussion on vitamin D included 2 studies from the U.S. Christine Dao and colleagues (abstract 750) presented findings from an analysis of 672 participants in the CDC's SUN study, which enrolled individuals with generally well-controlled HIV disease at clinics in 4 U.S. cities between 2004 and 2007. Most (77%) were men, the median age was 41 years, about 60% were white, 30% were black, and 10% were Hispanic. Three-quarters had HIV viral load < 400 copies/mL and the mean CD4 cell count was relatively high, at about 470 cells/mm3.

The researchers found that 72% of participants -- none of whom were receiving vitamin D supplements -- had insufficient blood levels of 25-hydroxyvitamin D. Factors associated with lower levels included black or Hispanic race/ethnicity, less sun exposure, high blood pressure, lack of exercise, and use of efavirenz (Sustiva, also in the Atripla combination pill), while impaired kidney function and use of ritonavir (Norvir) were protective.

Another study, by Audrey French and colleagues (abstract 750), looked at U.S. women, a cross-sectional analysis of 609 participants (79% HIV positive, 21% HIV negative) in the Women's Interagency Health Study (WIHS). In this analysis, 60% had vitamin D deficiency and 24% had insufficient levels. Black women were about 3 times more likely to have low levels than white women.

About 20% of the women had bacterial vaginosis (BV), or imbalance of the normal vaginal flora. The most frequent cause of vaginitis (vaginal inflammation), BV increases the risk of premature labor and susceptibility to HIV infection. Worsening vitamin D deficiency was strongly correlated with higher risk of BV. Black race and higher number of sex partners were also predictors of BV.

"Further study is needed to determine whether repletion of vitamin D will decrease the occurrence of BV," the researchers recommended.

European Studies

A pair of studies from Europe did not see such high rates of vitamin D deficiency as the U.S. studies. Christoph Fux, N. Mueller and colleagues (abstract 752) performed a retrospective analysis of 211 participants in the Swiss HIV Cohort. About 75% were men, the average age was 37 years, most (about 88%) were white, and the median CD4 count was about 225 cells/mm3.

Vitamin D levels were assessed before starting ART -- some measured during February-April (minimum sun exposure) and some during August-October (maximum sun exposure) -- and again 12 months (same season) and 18 months (opposite season) after treatment initiation.

Median blood calcidiol levels were substantially higher in the summer/fall than in the winter/spring (36.5 vs 57.4 nmol/L). Vitamin D deficiency was more common in the winter/spring than in the summer/fall (42% vs 14%), but the reverse was true for insufficiency (53% vs 62%). Levels did not change significantly at 1 year after starting treatment, but rose or fell as predicted during the opposite season.

Factors independently associated with lower vitamin D levels were black race, injection drug use, longer duration of HIV infection, and use of a NNRTI. Patients who used tenofovir (Viread, also in the Truvada and Atripla coformulations) had higher levels of the final active form, calcitriol, which was correlated with impaired kidney function (calcidiol is processed into calcitriol in the kidneys).

Marco Borderi and colleagues (abstract 751) looked at vitamin D levels in stored plasma samples from 856 HIV positive participants the Italian ICONA cohort (83% of samples taken while on ART, 17% prior to ART initiation). Almost all participants (93%) were from Italy, with only 3% from Africa.

Here, 54% of participants had vitamin D insufficiency and 7% had deficiency. Independent predictors of insufficiency included older age, non-European race/ethnicity, low body mass index, low CD4 count, and use of a NNRTI (versus a protease inhibitor).

These data seems to confirm, the researchers concluded, that "in HIV positive individuals, vitamin D insufficiency is predictive of the risk of subsequent development of a number of severe events such as cardiovascular, renal disease and diabetes."

African Study

Finally, Saurabh Mehta and colleagues (abstract 753) evaluated associations between vitamin D levels and health outcomes among nearly 900 pregnant women in Tanzania. Women with vitamin D insufficiency had almost a 200% higher risk of developing vaginal candidiasis (thrush), a 45% higher risk of wasting, a 28% higher risk of upper respiratory infections, and a 25% higher risk of progressing to WHO stage 3 or 4 HIV disease. Women with the lowest levels were more likely to experience other symptoms including mouth and throat sores and fatigue.

"Vitamin D status has a protective association with HIV disease progression and HIV-related complications during follow-up in HIV-infected women," the researchers concluded, suggesting that vitamin D supplementation could represent a simple and inexpensive method for improving health and quality of life, particularly in resource-limited settings.

Implications

Taken together, these studies indicate that vitamin D insufficiency is common among people with HIV. However, rates may not be much higher than those of the HIV negative general population; in the U.S. according to Dao, about three-quarters of the population may not get enough, similar to the 72% rate in the SUN study. Experts are increasingly aware that vitamin D deficiency is more common than previously believed, and many think current recommended levels are too low.

The CROI studies found various different factors to be associated with lower vitamin D levels, but black race and use of a NNRTI were consistent risk factors. Dao and colleagues noted that NNRTIs induce breakdown of calcidiol to inactive compounds in the liver via the cytochrome P450 enzyme system, resulting in vitamin D insufficiency.

Given the detrimental health consequences of vitamin D deficiency, the Swiss researchers recommended vitamin D screening for all HIV positive people; those with risk factors may benefit from supplementation.

Sun Study: CDC, Atlanta, GA; Abbott-Northwestern Hosp, Minneapolis, MN; Washington Univ in St Louis, Sch of Med, MO; Miriam Hosp, Providence, RI; Cerner Corp, Vienna, VA.

WHIS Study: Rush Univ Med Ctr, Chicago, IL; CORE Ctr, Stroger Hosp of Cook County, Chicago, IL; Columbia Univ Med Ctr, New York, NY; Montefiore Med Ctr, Bronx, NY.

Swiss Study: Univ Hosp Zurich, Switzerland; Univ Hosp Bern, Switzerland; Univ Hosp Basel, Switzerland; Cantonal Hosp, St Gallen, Switzerland; Ctr Hosp Univ Vaudois, Lausanne, Switzerland; Ospedale Civico di Lugano, Switzerland; Univ Hosp Geneva, Switzerland.

ICONA Study: S Orsola Hosp, Bologna, Italy; Gorizia Central Hosp, Italy; Royal Free and Univ College London Med Sch, London, UK; INMI L Spallanzani, Rome, Italy; Hosp Niguarda Ca Granda, Milan, Italy; San Martino Hosp, Genoa, Italy; San Bortolo Hosp, Vicenza, Italy; Infectious Disease Clin, Chieti, Italy; Univ of Bologna, Italy; San Paolo Hosp, Univ of Milan, Italy.

Tanzania Study: Harvard School of Public Health, Boston, MA; Muhimbili Univ of Hlth and Allied Sci, Dar es Salaam, Tanzania.

3/19/10

References

C Dao, P Patel, S Pals, and others (SUN Study Investigators). Assessment of Vitamin D Levels among HIV-infected Persons in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 750.

A French, O Adeyemi, D Agniel, and others. Vitamin D Deficiency and Bacterial Vaginosis among HIV-infected and -uninfected Women in the United States. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 754.

N Mueller, C Fux, B Ledergerber, and others. High Prevalence of Severe Vitamin D Deficiency in cART Naive and Successfully Treated Swiss HIV Patients. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 752.

M Borderi, F Vescini, A Cozzi-Lepri, and others. Prevalence of Hypovitaminosis D among HIV+ Patients Enrolled in a Large Italian Cohort. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 751.

S Mehta, D Spiegelman, F Mugusi, and others. Vitamin D and HIV-related Complications and HIV Disease Progression in Women in Tanzania. 17th Conference on Retroviruses and Opportunistic Infections (CROI 2010). San Francisco. February 16-19, 2010. Abstract 753.