the online version of this article ( doi:10.1007/s40121 - 015 - 0058-x ) contains supplementary material , which is available to authorized users . several new medications have become available to treat chronic hepatitis c ( hcv ) infection . these include drugs from several new direct - acting antiviral medication classes that are inhibitors of non - structural ( ns)3/4a serine protease and ns5b polymerase [ 1 , 2 ] . the treatment of chronic hcv infection has become more widely available given the approval of these medications . the clinical guidance for treating chronic hcv infection now typically includes multiple drugs : sofosbuvir ( sof ) or simeprevir ( sim ) in combination with other medications . the simultaneous use of multiple medications , polypharmacy , is associated with an increased likelihood of contraindicated drug  drug interactions ( xddi ) . important safety concerns arise when dealing with polypharmacy due to the increased potential of xddis among the chronic hcv - infected population . the majority of patients with chronic hepatitis c are between the ages of 5070  years and , as such , typically have developed age - related comorbidities that often necessitate management with chronic maintenance medications [ 5 , 6 ] . some of these medications may interact with hcv therapy and could potentially result in poor treatment outcomes including toxicity and incomplete therapy , which may lead to a diminished probability of achieving a sustained virologic response , or the development of resistance [ 7 , 8 ] . however , there is little data quantifying the excess frequency of xddis that occur between sim- or sof - containing treatment regimens when added to the existing medication profiles of hcv monoinfected patients . the majority of this work has been focused on patients with human immunodeficiency virus ( hiv)/hcv coinfection [ 9 , 10 ] . an understanding of the frequency and predictors of xddis when either sim- or sof - containing therapy is considered for initiation will aid clinicians in managing the most appropriate therapy for a given patient with hcv monoinfection . this study compares the expected occurrence of xddis when sim- or sof - containing therapy is added to medication profiles of patients with hcv monoinfection . secondly , this study identifies the predictors of xddis when sim- and sof - containing therapies are added to patient s home medication lists . a cross - sectional study was performed among hcv monoinfected veterans affairs patients receiving care between 2000 and 2013 in the upstate new york veterans healthcare administration ( vha ) or veterans integrated service network region 2 ( visn-2 ) . patients were identified using the following international classification of diseases 9th revision ( icd-9 ) codes related to hepatitis c infection : 070.41 ( acute hepatitis c with hepatic coma ) , 070.44 ( chronic hepatitis c with hepatic coma ) , 070.51 ( acute hepatitis c without mention of hepatic coma ) , 070.54 ( chronic hepatitis c without mention of hepatic coma ) , 070.70 ( unspecified hepatitis c without hepatic coma ) , and 070.71 ( unspecified hepatitis c with hepatic coma ) . each of these patients was screened to confirm hcv infection and for the following inclusion criteria : ( 1 ) age  18  years , ( 2 ) laboratory - confirmed hcv infection , and ( 3 ) availability of a medication list . patients with ( hiv ) were excluded because of the strong influence of antiretroviral therapy on the probability of xddis . data were obtained from the patients medical records related to demographics , concomitant medical problems , year hcv infection was diagnosed , and medication list . demographic characteristics included age , sex , race ( african american , hispanic , caucasian , and other ) , height and weight . concomitant medical problems were obtained from the clinical progress note . the most recent medication list in the patients medical records was obtained and used in this analysis . for each medication , the outcome of interest was the presence of xddis involving hcv therapy and the medications in the patient s most recent medication list ( home medications ) after the addition of either sim- or sof - containing regimens . sim , pegylated interferon , and ribavirin were used to define sim - containing therapy . analogously , sof - containing therapy was defined as sof , pegylated interferon and ribavirin . to define xddis , lexi - interact drug interaction software ( lexicomp , hudson , usa ) the drug  drug interactions that lexi - interact ranked as x - rated ( contraindicated ) were considered xddis . all of the patients home medications were entered into lexi - interact , and the number of xddis was recorded . then , sim - containing therapy was added to the existing home medications and the number of identified additional xddis was recorded . finally , sim - containing therapy was removed from lexi - interact and replaced with sof - containing therapy , and the number of additional xddis was recorded . to assess the data for the first study objective , mcnemar s test was used to compare the frequencies of xddis after adding sim- and sof - containing therapy to patients home medication profiles . for study objective # 2 ( predictors of xddi involving sim- and sof - containing therapy ) , bivariate analyses were performed to assess the relationship between the clinical covariates and xddis after the addition of a sim- and sof - containing hcv regimen to the patients medication lists . the student s t or mann  whitney u tests were used to compare continuous data . variables present in more than 5% of the population and associated with an xddi involving sim- and sof - containing therapy in the bivariate analyses ( p  <  0.25 ) were entered into the multivariate regression analyses . classification and regression tree ( cart ) analysis was used to identify thresholds in continuous variables at which the likelihood of an xddi distinctly differs . all calculations were computed using spss version 11.5 ( spss inc , chicago , il , usa ) , sas version 9.3 ( sas institute , cary , nc , usa ) , and cart software ( salford systems , san diego , ca , usa ) . this article does not contain any new studies with human or animal subjects performed by any of the authors . the mean    standard deviation ( sd ) age was 59.8    7.6  years . the majority ( n  =  4,102 , 96.5% ) of patients were male . caucasian race ( n  =  2,476 , 58.2% ) was observed most frequently , followed by african american ( n  =  1,219 , 28.7% ) , other ( n  =  438 , 10.3% ) , and hispanic ( n  =  118 , 2.8% ) . the median ( interquartile range , iqr ) number of years since hcv diagnosis was 12 ( 814 ) . the median ( iqr ) numbers of comorbidities and home medications used were 7 ( 510 ) and 7 ( 411 ) , respectively . the prevalence of xddi before the addition of sim- or sof - containing therapy was 16.7% ( n  =  709 ) . after the addition of sim- and sof - containing therapy , the overall prevalence of xddis significantly increased to 25.9% ( n  =  1,103 ) and 19.9% ( n  =  844 , p  <  0.001 ) , respectively . when restricting interactions to only those involving sim- or sof - containing therapy ( fig .  1 ) , the prevalence of xddis after the addition of these drugs was 12.6% ( n  =  535 ) and 4.7% ( n  =  201 , p  <  0.001 ) for sim- and sof - containing therapies , respectively . upon stratification by the cart - derived breakpoints ( < or 6 home medications and having < or 10 comorbidities ) , there were significant differences in the frequency of xddis involving hcv therapy between sim- and sof - containing regimens . the differences within each of the strata were consistent with the overall comparison in that sim - containing drugs tended to be associated with a greater likelihood of an xddi.fig . 1prevalence of contraindicated drug  drug interactions ( xddi ) involving hepatitis c therapy after addition of simeprevir- and sofosbuvir - containing therapy prevalence of contraindicated drug  drug interactions ( xddi ) involving hepatitis c therapy after addition of simeprevir- and sofosbuvir - containing therapy the bivariate analyses of xddis involving hcv medications after the addition of sim- and sof - containing therapies are described in table  1 . the variables associated with xddis involving sim - containing therapy were age , weight , time since hcv diagnosis , total number of home medications , and total number of comorbidities . specific home medication classes associated with xddi involving sim - containing therapy were antipsychotics , antibiotics , antiepileptics , azole antifungals , statins , calcium channel blockers , corticosteroids , central nervous system ( cns ) depressants , erectile dysfunction drugs , methadone , antiarrhythmic , corticosteroids , alpha or muscarinic-3 blockers , and beta-2 agonists . specific comorbidities associated with xddi involving sim - containing therapy were seizure disorder , arrhythmias , heart failure , heart disease , chronic kidney disease , recreational drug use , alcoholism , cancer , dementia , chronic obstructive pulmonary disorder , neuropathy , hypertension , organ transplant , and anemia.table  1bivariate analyses of clinical and demographic covariates associated with contraindicated drug  drug interactions ( xddi ) occurring with hcv therapy after addition of simeprevir- and sofosbuvir - containing therapycovariateno xddi after addition of sim  +  pr ( n  =  3,716)xddi after addition of sim  +  pr ( n  =  535)odds ratio ( 95% confidence interval ) 
 p valueno xddi after addition of sof  +  pr ( n  =  4,050)xddi after addition of sof  +  pr ( n  =  201)odds ratio ( 95% confidence interval ) 
 p valueage , mean    sd59.7    7.560.7    8.31.02 ( 1.011.03)0.00859.9    7.658.8    7.40.98 ( 0.961.00)0.05male sex , n ( % ) 3,593 ( 96.7)509 ( 95.1)1.49 ( 0.972.30)0.073,905 ( 96.4)197 ( 98.0)0.55 ( 0.201.50)0.32race , n ( % ) 1.00 ( 0.921.10)0.310.91 ( 0.791.04)0.45  african american1,060 ( 28.5)159 ( 29.7)1,152 ( 28.4)67 ( 33.3 )  caucasian2,173 ( 58.5)303 ( 56.6)2,364 ( 58.4)112 ( 55.7 )  hispanic108 ( 2.9)10 ( 1.9)114 ( 2.8)4 ( 2.0 )  other / unreported375 ( 10.1)63 ( 11.8)420 ( 10.4)18 ( 9.0)weight , mean    sd87.4    19.685.5    22.01.00 ( 0.991.00)0.0587.3  +  19.886.1    21.41.00 ( 0.991.00)0.40time since diagnosis of hcv , median ( iqr)12 ( 814)12 ( 914)1.02 ( 1.001.04)0.00712 ( 814)12 ( 914)1.02 ( 0.981.05)0.25medications  total number of home medications , median ( iqr)7 ( 410)10 ( 714)1.14 ( 1.121.16)<0.0017 ( 410)10 ( 714)1.12 ( 1.091.14)<0.001  use of  6 home medications , n ( % ) 2,171 ( 58.4)463 ( 86.5)4.58 ( 3.545.92)<0.0012,462 ( 60.8)172 ( 85.6)3.83 ( 2.575.70)<0.001  alpha or muscarinic-3 blocker , n ( % ) 259 ( 7.0)54 ( 10.1)1.50 ( 1.102.04)0.01225 ( 5.6)88 ( 43.8)13.23 ( 9.7218.04)<0.001  antiarrhythmics , n ( % ) 59 ( 1.6)20 ( 3.7)2.41 ( 1.444.03)0.00174 ( 1.8)5 ( 2.5)1.38 ( 0.553.43)0.50  antibiotics , n ( % ) 7 ( 0.2)15 ( 2.8)15.28 ( 6.2037.66)<0.00119 ( 0.5)3 ( 1.5)3.22 ( 0.9410.95)0.08  antidepressants , n ( % ) 576 ( 15.5)91 ( 17.0)1.12 ( 0.881.42)0.37611 ( 15.1)56 ( 27.9)2.17 ( 1.582.99)<0.001  antiepileptics , n ( % ) 10 ( 0.3)120 ( 22.4)107.16 ( 55.77205.90)<0.00139 ( 1.0)91 ( 45.3)85.08 ( 55.89129.52)<0.001  antipsychotics , n ( % ) 360 ( 9.7)100 ( 18.7)2.14 ( 1.682.73)<0.001414 ( 10.2)46 ( 22.9)2.61 ( 1.853.68)<0.001  azole antifungals , n ( % ) 1 ( 0.0)13 ( 2.4)92.52 ( 12.08708.70)<0.00112 ( 0.3)2 ( 1.0)3.38 ( 0.7515.21)0.09  beta-2 agonists , n ( % ) 15 ( 0.4)5 ( 0.9)2.50 ( 0.906.95)0.0719 ( 0.5)0 ( 0)na1.00  calcium channel blockers , n ( % ) 504 ( 13.6)206 ( 38.5)3.99 ( 3.274.86)<0.001674 ( 16.6)36 ( 17.9)1.09 ( 0.760.99)0.64  cns depressants , n ( % ) 1,223 ( 32.9)222 ( 41.5)1.44 ( 1.201.74)<0.0011,363 ( 33.7)82 ( 40.8)1.36 ( 1.021.81)0.04  corticosteroids , n ( % ) 579 ( 15.6)204 ( 38.1)3.34 ( 2.754.06)<0.001713 ( 17.6)70 ( 34.8)2.50 ( 1.853.38)<0.001  erectile dysfunction drugs , n ( % ) 775 ( 20.9)89 ( 16.6)0.76 ( 0.600.96)0.02816 ( 20.1)48 ( 23.9)1.24 ( 0.891.74)0.20  statins , n ( % ) 650 ( 17.5)117 ( 21.9)1.32 ( 1.061.65)0.01721 ( 17.8)46 ( 22.9)1.37 ( 0.981.92)0.07comorbidities  total number of comorbidities , median ( iqr)7 ( 510)8 ( 611)<0.0017 ( 510)8 ( 611)0.001  comorbidities 10 , n ( % ) 997 ( 26.8)201 ( 37.6)1.64 ( 1.361.98)<0.0011,121 ( 27.7)77 ( 38.3)1.62 ( 1.212.17)0.001  alcoholism , n ( % ) 1,477 ( 39.7)189 ( 35.3)0.83 ( 0.691.00)0.051,580 ( 39.0)86 ( 42.8)1.17 ( 0.881.56)0.29  anemia , n ( % ) 391 ( 10.5)88 ( 16.4)1.67 ( 1.302.15)<0.001458 ( 11.3)21 ( 10.4)0.92 ( 0.581.45)0.71  anxiety , n ( % ) 614 ( 16.5)75 ( 14.0)0.82 ( 0.641.07)0.14660 ( 16.3)29 ( 14.4)0.87 ( 0.581.30)0.48  arrhythmias , n ( % ) 163 ( 4.4)46 ( 8.6)2.05 ( 1.462.88)<0.001203 ( 5.0)6 ( 3.0)0.58 ( 0.261.33)0.19  asthma , n ( % ) 177 ( 4.8)28 ( 5.2)1.10 ( 0.731.66)0.64196 ( 4.8)9 ( 4.5)0.92 ( 0.471.83)0.82  bipolar , mood or personality disorder , n ( % ) 441 ( 11.9)79 ( 14.8)1.29 ( 0.99 1.67)0.06485 ( 12.0)35 ( 17.4)1.55 ( 1.06 2.26)0.02  cancer , n ( % ) 495 ( 13.3)125 ( 23.4)1.98 ( 1.592.48)<0.001583 ( 14.4)37 ( 18.4)1.34 ( 0.931.94)0.11  chronic kidney disease , n ( % ) 179 ( 4.8)66 ( 12.3)2.78 ( 2.063.75)<0.001235 ( 5.8)10 ( 5.0)0.85 ( 0.441.63)0.62  cirrhosis , n ( % ) 415 ( 11.2)62 ( 11.6)1.04 ( 0.791.39)0.77463 ( 11.4)14 ( 7.0)0.58 ( 0.331.00)0.05  chronic obstructive pulmonary disorder , n ( % ) 525 ( 14.1)103 ( 19.3)1.45 ( 1.151.83)0.002599 ( 14.8)29 ( 14.4)0.97 ( 0.651.45)0.88  dementia , n ( % ) 49 ( 1.3)15 ( 2.8)2.16 ( 1.203.88)0.00859 ( 1.5)5 ( 2.5)1.73 ( 0.694.35)0.24  depression , n ( % ) 1,549 ( 41.7)208 ( 38.9)0.89 ( 0.741.07)0.221,654 ( 40.8)103 ( 51.2)1.52 ( 1.152.02)0.003  diabetes , n ( % ) 992 ( 26.7)160 ( 29.9)1.17 ( 0.961.43)0.121,100 ( 27.2)52 ( 25.9)0.94 ( 0.681.29)0.69  dyslipidemia , n ( % ) 1,351 ( 36.4)211 ( 39.4)1.14 ( 0.951.37)0.171,492 ( 36.8)70 ( 34.8)0.92 ( 0.681.23)0.56  epilepsy or other seizure disorder , n ( % ) 115 ( 3.1)76 ( 14.2)5.19 ( 3.827.04)<0.001127 ( 3.1)64 ( 31.8)14.43 ( 10.2220.38)<0.001  erectile dysfunction , n ( % ) 857 ( 23.1)125 ( 23.4)1.02 ( 0.821.26)0.88925 ( 22.8)57 ( 28.4)1.34 ( 1.001.03)0.07  gastrointestinal reflux disease , n ( % ) 907 ( 24.4)141 ( 26.4)1.11 ( 0.901.36)0.331,000 ( 24.7)48 ( 23.9)0.96 ( 0.691.33)0.80  heart disease , n ( % ) 628 ( 16.9)112 ( 20.9)1.30 ( 1.041.63)0.02704 ( 17.4)36 ( 17.9)1.04 ( 0.721.50)0.85  heart failure , n ( % ) 110 ( 3.0)30 ( 5.6)1.95 ( 1.292.95)0.001133 ( 3.3)7 ( 3.5)1.06 ( 0.492.30)0.88  hepatitis b , n ( % ) 175 ( 4.7)32 ( 6.0)1.29 ( 0.871.90)0.20196 ( 4.8)11 ( 5.5)1.14 ( 0.612.13)0.68  history of myocardial infarction , n ( % ) 86 ( 2.3)7 ( 1.3)0.56 ( 0.261.22)0.1491 ( 2.2)2 ( 1.0)0.44 ( 0.111.79)0.24  homeless , n ( % ) 243 ( 6.5)28 ( 5.2)0.79 ( 0.531.18)0.25255 ( 6.3)16 ( 8.0)1.29 ( 0.762.18)0.35  hypertension , n ( % ) 2,097 ( 56.4)339 ( 63.4)1.34 ( 1.111.61)0.0022,321 ( 57.3)115 ( 57.2)1.00 ( 0.751.01)0.98  insomnia or other sleep disorders , n ( % ) 499 ( 13.4)73 ( 13.6)1.02 ( 0.781.33)0.89549 ( 13.6)23 ( 11.4)0.82 ( 0.531.28)0.39  methadone , n ( % ) 68 ( 1.8)18 ( 3.4)1.87 ( 1.103.17)0.0281 ( 2.0)5 ( 2.5)1.25 ( 0.503.12)0.63  neuropathy , n ( % ) 425 ( 11.4)78 ( 14.6)1.32 ( 1.021.72)0.04466 ( 11.5)37 ( 18.4)1.74 ( 1.202.51)0.003  organ transplant , n ( % ) 33 ( 0.9)27 ( 5.0)5.93 ( 3.549.95)<0.00158 ( 1.4)2 ( 1.0)0.69 ( 0.172.85)1.00  osteoporosis , osteoarthritis or osteogenesis , n ( % ) 776 ( 20.9)127 ( 23.7)1.18 ( 0.951.46)0.13865 ( 21.4)38 ( 18.9)0.86 ( 0.601.23)0.41  peripheral vascular disease , n ( % ) 239 ( 6.4)44 ( 8.2)1.30 ( 0.931.82)0.12271 ( 6.7)12 ( 6.0)0.89 ( 0.491.61)0.69  post - traumatic stress disorder , n ( % ) 899 ( 24.2)127 ( 23.7)0.98 ( 0.791.21)0.82936 ( 23.1)90 ( 44.8)2.70 ( 2.023.60)<0.001  prostate disease , n ( % ) 627 ( 16.9)101 ( 18.9)1.15 ( 0.911.45)0.25692 ( 17.1)36 ( 17.9)1.06 ( 0.731.53)0.76  recreational drug use , n ( % ) 2,576 ( 69.3)329 ( 61.5)0.71 ( 0.590.85)<0.0012,758 ( 68.1)147 ( 73.1)1.28 ( 0.931.75)0.13  schizophrenia or psychosis , n ( % ) 269 ( 7.2)44 ( 8.2)1.15 ( 0.821.60)0.42294 ( 7.3)19 ( 9.5)1.33 ( 0.822.17)0.25  thyroid disease , n ( % ) 277 ( 7.5)44 ( 8.2)1.11 ( 0.801.55)0.53310 ( 7.7)11 ( 5.5)0.70 ( 0.381.30)0.25  transient ischemic attack or other cardiovascular history , n ( % ) 152 ( 4.1)31 ( 5.8)1.44 ( 0.972.15)0.07171 ( 4.2)12 ( 6.0)1.44 ( 0.792.63)0.23data presented are restricted to xddis involving sim- or sof - containing regimens and not underlying xddis involving patients home medications . all data presented as n ( % ) , median ( interquartile range ) and mean    standard deviation unless otherwise indicated 
 sim  +  pr simeprevir  +  pegylated interferon and ribavirin , sof  +  pr sofosbuvir  +  pegylated interferon and ribavirin , iqr interquartile range , sd standard deviation , xddi contraindicated drug drug interaction bivariate analyses of clinical and demographic covariates associated with contraindicated drug  drug interactions ( xddi ) occurring with hcv therapy after addition of simeprevir- and sofosbuvir - containing therapy data presented are restricted to xddis involving sim- or sof - containing regimens and not underlying xddis involving patients home medications . all data presented as n ( % ) , median ( interquartile range ) and mean    standard deviation unless otherwise indicated 
 sim  +  pr simeprevir  +  pegylated interferon and ribavirin , sof  +  pr sofosbuvir  +  pegylated interferon and ribavirin , iqr interquartile range , sd standard deviation , xddi contraindicated drug these included age , total number of home medications , antipsychotics , antidepressants , antiepileptic drugs , cns depressants , corticosteroids , alpha or muscarinic-3 blocker , total number of comorbidities , bipolar / mood / personality disorder , depression , seizure disorder , post - traumatic stress disorder , neuropathy , and cirrhosis . the use of  6 home medications and having  10 comorbidities was associated with an increased frequency of xddi involving either sim- or sof - containing therapy . in multivariable analyses examining the predictors of xddis involving sim - containing therapy , the only medication - related predictor was use of  6 home medications ( odds ratio or 4.58 , 95% confidence interval ci 3.545.20 , p  <  0.001 ) . similarly , the use of  6 home medications was also the only variable associated with an increased probability of xddi involving sof - containing therapy ( or 3.83 , 95% ci 2.575.70 , p  <  0.001 ) . to make the models more specific , the use of  6 home medications was replaced with the medication classes associated with xddi involving either sim- or sof - containing therapy . variables independently associated with xddi involving sim - containing therapy were calcium channel blockers , corticosteroids , antipsychotics , antiarrhythmic , and cns depressants . variables independently associated with xddis involving sof - containing therapy were corticosteroids , antipsychotics , antidepressants , and statins.table  2variables independently associated with contraindicated drug  drug interactions after the addition of simeprevir- or sofosbuvir - containing hepatitis c therapyvariableodds ratio95% confidence interval 
 p valuexddi after addition of simeprevir - containing therapy  calcium channel blockers4.153.385.11<0.001  corticosteroids3.412.784.19<0.001  antipsychotics2.531.963.28<0.001  antiarrhythmics2.231.283.890.005  central nervous system depressants1.321.091.610.005xddi after addition of sofosbuvir - containing therapy  corticosteroids2.541.873.440.001  antipsychotics2.441.713.480.001  antidepressants1.901.372.640.001  statins1.401.001.970.05 variables independently associated with contraindicated drug  drug interactions after the addition of simeprevir- or sofosbuvir - containing hepatitis c therapy therapies containing sim or sof are associated with a high cost and it is imperative that clinicians take appropriate measures to ensure that patients have the highest likelihood of completing therapy , achieving a sustained virologic response and minimizing adverse events . in some situations , adverse events that are a function of xddis can be prevented by proactively identifying patients at risk for xddis prior to prescribing sim or sof - containing therapy and choosing the type of therapy that is associated with a lower probability or using them in patients who do not have risk factors for xddis . this intervention , coupled with optimal drug adherence , can contribute to the probability of a good treatment outcome . the majority of other population - based drug drug interaction studies have been focused on patients with hiv / hcv coinfection [ 9 , 10 ] . the results presented here are consistent with other publications [ 4 , 9 , 10 , 15 ] . it was observed that polypharmacy was an issue among patients with hcv monoinfection and these patients are vulnerable to the effects of xddi . patients in the study were using a median of seven home medications , and over 15% of patients had xddis involving medications that they were already taking and before the addition of sim- or sof - containing therapy . this is important because several other patient populations ( hiv , transplant , dialysis , etc . ) are considered high risk for xddis and now , given these data , patients with hcv monoinfection should be considered as well [ 1518 ] . patients with hcv monoinfection may need pharmacotherapeutic intervention to resolve any existing xddis before being prescribed sim- or sof - containing therapy . it was also observed that sim - containing regimens were associated with nearly triple the likelihood of xddis compared to sof - containing regimens . these results are plausible given that sim is a cyp3a hepatic substrate and intestinal inhibitor . there may be altered exposure of both sim and other drugs that also utilize these enzymatic pathways when used concomitantly . conversely , sof is metabolized by p - glycoprotein ( p - gp ) , a less ubiquitously utilized metabolic pathway , and sof exposure may be altered in the presence of other p - gp inducers / inhibitors . many xddis involving either type of hcv therapy were predicted by use of various drug classes . these data demonstrate the need for a pharmacist to review patients medications before hcv therapy is prescribed . to appropriately interpret these data , rather , sim- and sof - containing therapy was added to the home medication lists of the patients in the study to assess what proportion would have an xddi if either of these regimens were prescribed . this is strength of the paper , because it demonstrates how a counterfactual study design allows the evaluation of an outcome of interest in the same patient under two exposure conditions . second , patients with hiv were excluded because antiretroviral therapy is an exceptionally strong predictor of drug  drug interactions . apart from the use of anti - retrovirals , it was also unclear if medication use patterns differed between coinfected and monoinfected patients . because of these issues , it was felt that inclusion of patients with hiv / hcv coinfection would mask some of the non - hiv - related predictors of xddi involving sim- or sof - containing therapy . to preserve internal validity , the choice to restrict the study population to only those with hcv monoinfection was made . third , liver performance [ fibrosis / alanine transaminase ( alt ) , etc . ] was not known and this , as well as other markers or disease severity , may be associated with higher medication use and subsequent risk of xddis . future studies should attempt to assess the contribution of markers of disease severity and determine if variables such as time since hcv diagnosis are truly associated with a higher probability of medication use and xddis . fourth , some of the predictors , particularly for xddi involving sof - containing therapy , are not drug classes that are contraindicated with sof - containing therapy in the product labeling . it is important to note that patients receiving these drug classes were more likely to have an xddi involving sof - containing therapy , although these classes are contraindicated themselves . more than likely , these predictors may be indicative of xddis that may exist prior to the addition of hcv therapy or a proxy for other variables such as disease severity , whereby patients may require the use of several medications to control other underlying comorbidities . the regimens we evaluated contained interferon and ribavirin in combination with either sim or sof . it is important to note that interferon and ribavirin are associated with few xddis and the majority of interactions were driven in large part due to sim or sof . this study will need to be repeated in the future with emerging agents like ledipasvir , ombitasvir , dasabuvir , and daclatasvir . in summary , the results of this study found that hcv monoinfected patients are at high risk for xddis , and sof - containing therapy had a lower frequency of xddis than sim - containing therapy . polypharmacy with various classes of home medications predicted xddis involving sim- or sof - containing therapy . clinicians prescribing either of these treatment regimens should thoroughly evaluate patients existing medications to avoid potential xddis . mona nasiri , arden koroglu , steven bliss , melissa davis , louise - anne mcnutt , and christopher miller declare that they have no conflicts of interest . this article does not contain any new studies with human or animal subjects performed by any of the authors . this article is distributed under the terms of the creative commons attribution noncommercial license which permits any noncommercial use , distribution , and reproduction in any medium , provided the original author(s ) and the source are credited .
introductionthis study compares the expected occurrence of contraindicated drug  drug interactions ( xddis ) when simeprevir ( sim)- or sofosbuvir ( sof)-containing therapy is added to medication profiles of patients with hepatitis c ( hcv ) monoinfection to quantify , in relative terms , the population - based risk of xddis . 
 second , this study identified the predictors of xddis when hcv therapies are added to medication profiles.methodsa cross - sectional study was performed among veterans affairs patients . 
 inclusion criteria were : ( 1 ) age  18  years , ( 2 ) hcv infection , and ( 3 ) availability of a medication list . 
 patients with human immunodeficiency virus were excluded . 
 demographics , comorbidities , year of hcv diagnosis , and most recent medication list were collected from medical records . 
 the primary outcome was the presence of xddis involving hcv therapy and the medications in the patient s home medication list after the addition of either sim- or sof - containing regimens . to define xddis , lexi - interact drug interaction software was 
 used.results4,251 patients were included . 
 the prevalence of xddis involving sim- or sof - containing therapy were 12.6% and 4.7% ( p  <  0.001 ) , respectively . in multivariable analyses examining the predictors of xddis involving sim - containing therapy , the only medication - related predictor was use of  6 home medications ( odds ratio or 4.58 , 95% confidence interval ci 3.545.20 , p  <  0.001 ) . 
 similarly , use of  6 home medications was also the only variable associated with an increased probability of xddi involving sof - containing therapy ( or 3.83 , 95% ci 2.575.70 , p  < 
 0.001).conclusionssofosbuvir - containing therapy had a lower frequency of xddis than sim - containing therapy . 
 polypharmacy with various classes of home medications predicted xddis involving sim- or sof - containing therapy.electronic supplementary materialthe online version of this article ( doi:10.1007/s40121 - 015 - 0058-x ) contains supplementary material , which is available to authorized users .