clinicians and researchers are currently using available data sets to assess the balance of beneficial and harmful effects of vitamin d not only on skeletal health but also on its potential role in nonskeletal outcomes such as cardiovascular disease , death , and quality of life [ 13 ] . the effects of vitamin d on immune function   and its immunomodulatory and anti - inflammatory properties have been recognized , and a nontraditional role of vitamin d has been reported in cancer patients and autoimmune disease [ 46 ] . these effects have also been reported in chronic liver disease and among chronic hepatitis c patients in whom vitamin d is involved in regulating the immune system , inflammatory response , and fibrogenesis [ 710 ] . recently , low 25-hydroxyvitamin d serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis c patients ( g1chc ) [ 11 , 12 ] . in vitro studies have shown that vitamin d is an antiviral agent that inhibits hcv production in a human hepatoma cell line ; a synergistic effect of vitamin d and interferon - alfa on hcv production has also been reported . in hcv monoinfected patients with recurrent hepatitis c after liver transplant , higher rates of virologic response were observed in those receiving vitamin d supplementation . finally , in a randomized prospective trial including only chc treatment - naive hcv - genotype ( hcv - gt ) 1 patients , virologic response rates were again higher in the group receiving vitamin d supplementation . hepatitis c virus ( hcv ) infection has become a major health problem among the hiv - infected population [ 15 , 16 ] . approximately 30% of all human immunodeficiency virus ( hiv- ) positive patients are also infected with hepatitis c virus ( hcv ) [ 1618 ] . among the multifactorial mechanisms underlying skeletal disorder in the hiv and hcv setting , vitamin d deficiency is considered a risk factor for osteoporotic fracture [ 7 , 1820 ] ; moreover , the finding that hcv - related increased fracture risk is a function of the severity of liver disease has generated a lot of attention so far [ 7 , 2123 ] . the fact that hiv and hiv / hcv coinfected patients are at risk of vitamin d deficiency because a wide variety of medications used to treat aids / hiv enhance the catabolism of 25(oh)d and 1,25(oh ) 2d [ 23 , 24 ] has been acknowledged . vitamin d deficiency and bone disease in haart patients   have been associated with nnrtis , as well as tenofovir   and pis [ 27 , 28 ] . while there are recommendations for the evaluation , treatment , and prevention of vitamin d deficiency in healthy patients at risk of deficiency [ 3 , 24 ] and in specific hiv populations such as young hiv - positive adults with 25-hydroxyvitamin d ( 25-ohd ) < 20  ng / ml , there is still some debate about the evaluation , treatment , and prevention of vitamin d deficiency in the hiv population   and in particular in hiv / hcv coinfected subjects [ 7 , 8 , 31 , 32 ] . finally , recent literature offers recommendations on screening and treating vitamin d deficiency and osteoporosis in hiv - positive patients   but there is not a great deal of literature and/or consensus on cost - effective management of this patient population , especially hiv / hcv coinfected patients [ 22 , 3133 ] . this paper aims to summarize the prevalence of vitamin d deficiency in hiv / hcv coinfected patients , review available data on the association between vitamin d levels and severity of liver disease , and discuss the impact of this relatively inexpensive therapy on reducing liver fibrosis and improving sustained virologic response rate ( svr ) in hcv patients . we searched the medline ( pubmed ) database for articles that matched any combination of the following keywords : vitamin d , vitamin d deficiency , 25-hydroxyvitamin d , hiv / hcv coinfections and diagnosis and treatment , and hypovitaminosis . studies were identified through searching medline and embase databases , from their inception to august 2014 . articles were screened and those that reported on the relationship between vitamin d insufficiency / deficiency and hiv / hcv coinfections were included . we limited the search to language ( i.e. , spanish , french , or english ) and abstract availability . because the terms hiv infection and hiv / hcv infection are frequently associated in the scientific literature , for this study the term hiv / hcv coinfections was used as a medical subject heading ( mesh ) and the other terms ( together with their linguistic variations ) were used as keywords . some articles that appeared with keyword searching were excluded because they were not relevant to the purpose of this review and tackled other topics such as anti - hcv therapy in hiv / hcv coinfected patients . forty - four studies fit the criteria ; 15 of these were duplicates and were removed . after screening titles and abstracts , we excluded 9 articles on studies involving hcv monoinfected or hiv monoinfected participants . applying the eligibility criteria , we selected 12 studies ( see table 1 ) : 10 original [ 21 , 3139 ] , 1 systematic review and meta - analysis article , and 1 review manuscript . we found 5 cross - sectional [ 31 , 32 , 35 , 37 , 39 ] , 3 retrospective [ 21 , 34 , 36 ] , and 2 prospective cohort studies [ 33 , 38 ] ; most control groups included patients with hiv - mono- or hcv - monoinfection . overall , the articles were highly heterogeneous in terms of sample size , participant recruitment , and data source ( table 1 ) . the patients ' age in all the studies is relatively homogenous ( median age 45 years old ) , reflecting the worldwide aging of the hiv population after the widespread availability of combination antiretroviral therapy ( cart ) . in general , the articles analyzed the prevalence of vitamin d levels in hiv / hcv coinfected patients and the association between vitamin d deficiency and liver disease variables such as severity of liver disease [ 21 , 32 , 34 , 39 ] and the influence of vitamin d levels on virological response [ 32 , 35 , 36 ] . in fact , two recent studies showed a significant association between hypovitaminosis d , severity of liver disease , and response to interferon- ( ifn- ) based treatment in hiv - hcv patients [ 11 , 35 ] . however , the association between 25(oh)d levels and svr rates is thought to be limited to difficult - to - treat patients in whom treatment failure may depend on other factors ( il28 b , hcv genotype , hepatic expression of vitamin d receptor ) [ 11 , 12 , 33 , 35 ] . in their hiv / found that baseline levels of 25(oh)d in patients treated with ritonavir are not predictors of evr and svr because ritonavir may influence conversion of 25(oh)d to the active metabolite . other articles showed a significant negative association between longer duration of art , especially pi exposure and bone mineral density ( bmd ) and osteoporosis [ 22 , 28 , 38 ] . however , in one large cohort study , hcv coinfection remained an independent predictor of osteoporotic fractures after checking for the presence of cirrhosis [ 21 , 22 ] . two articles [ 33 , 39 ] showed no association between hypovitaminosis d , low bmd , and liver fibrosis ( histological fibrosis staging according to metavir scores 0 [ no fibrosis ] to 4 [ cirrhosis ] ) in hiv / hcv coinfected patients . the analysis of patient setting showed that most of the study populations included hiv / hcv coinfected african americans . how race affects the impact of vitamin d on bone health has recently been investigated in african american men and women , revealing differences due to socioeconomic and genetic factors , such as resistance to the bone resorbing effects of pth in the black population [ 33 , 4042 ] . 's study   had hcv gt1 genotype and low levels of vitamin d that varied seasonally , as reported in another italian study . on the contrary , avihingsanon et al .   found significant liver fibrosis in patients with hiv / hcv coinfection and low levels of 25(oh)d . these results may be influenced by race ( asian ) , hcv genotype ( gt ) [ the most prevalent circulating genotype was hcv gt3 ( 47% ) ] , and il28b polymorphism ( the major allele [ cc genotype ] of rs12979860 position was found in 88% of hiv / hcv patients ) . regarding the prevalence of fracture in this group of patients with liver disease , dong et al . 's systematic review and meta - analysis   highlights that fracture incidence rate ratios ( irrs ) are higher for coinfected than hiv monoinfected and uninfected patients . in multivariate analyses of hiv / hcv coinfected individuals , older age , lower bmi , postmenopausal status , and time on protease inhibitor were significantly associated with osteoporosis [ 1820 , 22 , 27 , 28 , 38 ] . among the hiv / hcv coinfected patients , haemophiliacs are considered to be at the highest risk for fracture . the authors divided 78 haemophiliac patients into three groups ( uninfected , hiv monoinfected , and hiv / hcv coinfected ) ; hypovitaminosis d and low bmd were present in all patients , with lower l - dxa scores in coinfected patients and a more evident increase of bone resorption markers in hiv and hiv / hcv coinfected patients . our literature review indicated that vitamin d deficiency is common in hiv / hcv coinfected patients and that hypovitaminosis d occurrence among patients with an average age of 45 years should raise concerns about the risk of developing bone fractures . low levels of vitamin d were also found in hiv monoinfected [ 21 , 38 , 39 ] and hcv monoinfected control groups [ 32 , 37 ] . however , the selected articles reveal some aspects that prompt us to reconsider the definition of hypovitaminosis d. in fact , the significance of vitamin d deficiency has several limitations because 25-hydroxyvitamin d concentrations varied by age , season , study sample size , and methodological assay approach [ 25(oh)d assay used ] [ 37 , 39 , 40 ] . moreover , black and hispanic individuals synthesize less vitamin d per unit of sun exposure than white individuals [ 33 , 41 , 42 ] . therefore , levels of vitamin d in hiv / hcv coinfected patients should be monitored according to the reference range for the sample setting . in fact , further validation of the reported results is needed , since studies conducted on larger cohorts , as well as in italian coinfected patients , have revealed low vitamin d levels consistent with those recently reported for healthy populations from western countries [ 38 , 39 , 43 ] . found that season and severity of fibrosis were predictors of low 25(oh)d in an italian hiv / hcv coinfected population and that median 25(oh)d serum levels below 25  ng / ml were similar in the hiv monoinfected , hiv / hcv coinfected , and healthy controls . in a recent , large study on a general healthy population in central europe , pludowski et al . guidelines specify that 25(oh)d concentrations are the best indicator of overall vitamin d status in the general population and define vitamin d insufficiency as a 25(oh)d level of below 75  nmol / l ( 30  ng / ml ) and deficiency as below 50  nmol / l ( 20  ng / ml ) . however , the endocrine society clinical practice guidelines ( escpg ) suggest that the vitamin d requirements of sick patients may be greater than those of healthy individuals , and blood levels above 30  ng / ml may carry additional health benefits by reducing the risk of various disease conditions [ 24 , 40 ] . the hormone foundation 's patient guide to vitamin d deficiency suggests that patients with chronic ( long - term ) liver disease are at high risk of deficiency ; therefore vitamin d testing is recommended and patients should be given advice about adequate dietary intake and medical supplementation to prevent and treat deficiency . the influence of diet on vitamin d status is minimal ( accounting for 3.75.9  g or 148236 iu daily ) as only a few foods , such as sardines , tuna , and mushrooms , naturally contain vitamin d [ 24 , 40 ] . today , the main sources are foods which have been fortified with vitamin d2 and/or vitamin d3 , such as milk , orange juice , yoghurt , cheese , and breakfast cereals , which people of all ages can include in their daily diet . although it has been suggested that a mediterranean - style diet or a diet rich in fish and other foods containing vitamin d has health benefits , further evaluation is necessary [ 24 , 38 , 44 , 45 ] . our selected articles investigated the possibility of an association between vitamin d deficiency and hepatic fibrosis in hiv / hcv coinfected patients . hcv coinfected patients showed that increasing vitamin d levels does not improve bone or liver outcome , whereas other studies illustrate how vitamin d influences virological response to antiviral treatment in hiv - hcv coinfected patients and has a role in liver fibrosis progression [ 31 , 34 , 35 ] . older and more recent research has investigated the link between vitamin d homeostasis and bone loss in patients with liver disease [ 7 , 8 , 22 , 46 ] . vitamin d deficiency in chronic liver disease is only partly the result of a synthesis dysfunction of the liver or / and decreased vitamin d absorption caused by intestinal edema due to portal hypertension or to cholestasis . recently , significantly lower levels of 25-hydroxyvitamin d were observed in patients with liver cirrhosis , admitted for acute decompensation , suggesting that systemic inflammation or liver dysfunction has an impact on 25(oh)d level . regarding vitamin d synthesis , parathyroid hormone ( pth ) is involved in its activity and expression ; disturbance of the parathyroid hormone - vitamin d axis with bone mass loss in chronic liver disease has recently been reported in cirrhotic postmenopausal women and in geriatric patients with vitamin d deficiency [ 47 , 48 ] . a systematic review and meta - analysis included in our literature review found that hiv / hcv - coinfected patients are at higher risk for osteoporosis and fractures than hiv - monoinfected controls and are at a substantially higher risk than uninfected controls . hcv and hiv infections are both associated with increased levels of proinflammatory cytokines that can promote osteoclastogenesis or inhibit osteoblast differentiation and collagen synthesis [ 7 , 8 , 22 ] . the mechanisms responsible for osteopenia and osteoporosis are uncertain and multifactorial , but exposure to certain antiretroviral drugs ( in particular a nrti : tenofovir - tdf - and the pi class ) , aging , hiv itself , parathormone ( pth ) increase , and vitamin d deficiency may be implicated . moreover , in a cohort of g1chc patients , the hepatic expression of vdr protein is associated with severity of both liver fibrosis and inflammation [ 12 , 34 ] . guidelines for the management of osteoporosis in hiv - negative [ 3 , 24 , 40 , 44 ] and hiv - positive patients identified adequate vitamin d status , in addition to calcium from diet or supplements , as essential for the prevention of osteoporosis [ 24 , 29 , 30 , 49 ] . adjunct therapy with high - dose , daily vitd3 for hiv - infected subjects and for those on / off highly active antiretroviral therapy was recently investigated in a high - risk , adult hiv - infected group and in hiv - infected children [ 29 , 49 ] . however , these levels have not been supported by adequate dose - finding rtc studies . future interferon - free direct - acting agents may have a better effect on bone metabolism and decrease fracture incidence after successful treatment . although the risk of fracture is clearly higher in hiv / hcv coinfected individuals , it is not clear if dxa screening of these individuals before the age of 50 is a cost - effective prevention method and requires further study . lifestyle - related factors appear to have a substantial impact on the risk of fractures in hiv / hcv coinfected individuals but , based upon available studies , this can not solely be attributed to alcohol and substance use [ 22 , 38 ] . recent data indicate that vitamin d supplementation is a relatively inexpensive therapeutic option to reduce liver fibrosis and improve svr [ 22 , 34 ] . interestingly , two potentially modifiable factors , cd4 + nadir and serum 25(oh)d levels , were both independent modulators of liver fibrosis progression and determinants of portal pressure . currently , practitioners are often concerned about the lack of well - characterized data on the therapeutic value of vitamin d supplementation to reduce liver fibrosis progression in hiv / hcv coinfected patients . increasing vitamin d intake may positively modulate response to antiviral treatment in hcv - infected or hiv / hcv coinfected patients , and , in association with standardized treatment for chronic liver disease , it could be of benefit in reducing liver fibrosis progression in hiv / hcv coinfected patients . in general , there is no evidence to suggest that increasing the recommended vitamin d intake for the general population to 2050  g ( 8002000  iu ) would cause any medical problems . however , the authors recommend careful clinical observation and laboratory monitoring when higher doses of vitamin d supplements are administered because of the long half - life of vitamin d accumulation in tissues ; excessive intake of vitamin d can cause chronic toxic effects , which present ashypercalcemia and renal damage . further controlled randomized trials on the effects of vitamin d supplementation are warranted to assess the relevance of vitamin d for liver fibrosis progression in hiv / hcv coinfected patients . our review indicates that vitamin d supplementation can be considered a relatively inexpensive therapeutic option to lower hcv - related fracture risk , owing to its benefic effect in reducing liver fibrosis progression in hiv / hcv coinfected patients . a good compromise between different opinions could be to start with relatively higher doses of vitamin d in hiv - hcv infected patients , skipping some steps of dose supplementation until more information is available to settle the question . experimental evidence suggested a hepatoprotective role of vitamin d.practitioners are often concerned about the lack of well - characterized data on the therapeutic value of vitamin d supplementation to reduce liver fibrosis progression in hiv / hcv coinfected patients . 
  experimental evidence suggested a hepatoprotective role of vitamin d. practitioners are often concerned about the lack of well - characterized data on the therapeutic value of vitamin d supplementation to reduce liver fibrosis progression in hiv / hcv coinfected patients . what is new ? 
 only particularly low levels of vitamin d should be considered in hiv / hcv coinfected patients.this systematic review reveals a recent interest in vitamin d supplementation as a relatively inexpensive therapeutic option to reduce hcv - related increased fracture risk by modifying liver fibrosis progression . only particularly low levels of vitamin d should be considered in hiv / hcv coinfected patients . this systematic review reveals a recent interest in vitamin d supplementation as a relatively inexpensive therapeutic option to reduce hcv - related increased fracture risk by modifying liver fibrosis progression . what does this mean ? 
 among hiv - infected patients , the association between 25(oh)d levels and severity of liver disease partly explains the hcv - associated increased risk of osteoporotic fractures , while other determinants have still to be defined.further rcts are warranted to determine what level of vitamin d insufficiency and deficiency places an individual at risk of cirrhosis evolutions and what is the optimal dosage of vitamin d3 to exert sufficient antifibrosis effects in hiv / hcv coinfected populations . 
  among hiv - infected patients , the association between 25(oh)d levels and severity of liver disease partly explains the hcv - associated increased risk of osteoporotic fractures , while other determinants have still to be defined . further rcts are warranted to determine what level of vitamin d insufficiency and deficiency places an individual at risk of cirrhosis evolutions and what is the optimal dosage of vitamin d3 to exert sufficient antifibrosis effects in hiv / hcv coinfected populations .
vitamin d deficiency further increases the risk of osteoporosis in hiv - positive patients coinfected with hepatitis c virus ( hcv ) ; however , it is still unclear whether hcv - related increased fracture risk is a function of the severity of liver disease . 
 the aim of this review was to identify studies on associative vitamin d deficiency patterns in high - risk populations such as hiv / hcv coinfected patients . 
 we did this by searching medline and embase databases , from inception to august 2014 , and included bibliographies . 
 the final 12 articles selected are homogeneous in terms of age but heterogeneous in terms of sample size , participant recruitment , and data source . 
 most of the hiv / hcv coinfected patients have less than adequate levels of vitamin d. after reviewing the selected articles , we concluded that vitamin d deficiency should be regarded as a continuum and that the lower limit of the ideal range is debatable . 
 we found that vitamin d deficiency might influence liver disease progression in hiv / hcv coinfected patients . 
 methodological issues in evaluating vitamin d supplementation as a relatively inexpensive therapeutic option are discussed , as well as the need for future research , above all on its role in reducing the risk of hcv - related fracture by modifying liver fibrosis progression .