we evaluated rates of sustained virologic response 12 weeks after the end of treatment ( svr12 ) , adverse events , and graded laboratory abnormalities in black versus nonblack subjects in the phase 3 ion program .
the ion1 , ion2 , and ion3 clinical trials evaluated the safety and efficacy of 8 , 12 , and 24 weeks of the fixeddose combination of ledipasvir and sofosbuvir with or without ribavirin for treatment of genotype1 chronic hcv .
there was no upper limit to age or body mass index ( bmi ) , and the primary endpoint was svr12 for all trials .
the ion1 trial was a phase 3 openlabel study involving 865 ( 16% cirrhotic ) previously untreated patients with chronic hcv . in the ion1 trial , patients were randomly assigned to four arms in a 1:1:1:1 ratio to receive ledipasvir / sofosbuvir in a fixeddose combination tablet once daily for 12 weeks ( with or without ribavirin ) or for 24 weeks ( with or without ribavirin).12 
  the ion2 clinical trial was structured similarly to the ion1 trial ; however , it was a phase 3 , randomized openlabel study involving 440 patients ( 20% cirrhotic ) infected with hcv genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin , with or without a protease inhibitor.13 similar to the ion1 trial , patients in the ion2 trial were randomly assigned to receive ledipasvir and sofosbuvir in a oncedaily , fixeddose combination tablet for 12 or 24 weeks with or without ribavirin .
given the high svr12 rates seen at 12 weeks for the ion1 and ion2 trials , the ion3 trial was devised to evaluate svr after 8 weeks of treatment.14 ion3 was an openlabel study with random assignment of 647 previously untreated patients with hcv genotype 1 infection without cirrhosis to receive the combination of ledipasvir and sofosbuvir with or without ribavirin for 8 weeks or ledipasvir / sofosbuvir for 12 weeks . using pooled data from the ion trials , we performed an integrated ad hoc analysis to evaluate the efficacy and safety of ledipasvir / sofosbuvir with or without ribavirin in black versus nonblack patients .
descriptive summaries were provided by race ( black or nonblack ) for the key demographics and baseline characteristics , including age , sex , bmi , il28b genotype , and so forth .
the svr12 rate and the twosided 95% exact confidence interval ( clopperpearson method ) were calculated by race ( black or nonblack ) and for each subgroup defined by prior hcv treatment experience ( treatmentnave or treatmentexperienced ) , cirrhosis status ( cirrhotic versus noncirrhotic ) , and baseline hcv rna ( < 6 or 6 million iu / ml ) .
safety data were analyzed by the number and percent of black versus nonblack patients experiencing adverse events .
of the 1952 patients randomized and treated in the ion studies , 308 ( 16% ) selfreported their race as black .
of the remaining 1644 patients in these studies , three declined to report race , leaving 1641 nonblack patients for comparison in this analysis .
overall , approximately one quarter of the patients had a bmi 30 kg / m ; this proportion was considerably higher among black patients than it was among nonblack patients ( 41% versus 23% ) .
overall , 12% of patients , but only 7% of blacks , had compensated cirrhosis . as expected , more blacks had noncc il28b genotypes than nonblacks ( 90% versus 73% ) . the mean alanine aminotransferase level for blacks ( 61
u / l ) was lower than that of nonblacks ( 77 u / l ) . among the ion study participants ,
similar proportions of black and nonblack patients were treatmentexperienced and had hcv rna 800,000 iu / ml . abbreviations : alt , alanine aminotransferase ; bmi , body mass index ; egfr , estimated glomerular filtration rate ; hcv , hepatitis c virus .
overall , 95% of black patients ( 95% confidence interval [ ci ] , 92%97% ) and 97% of nonblack patients ( 95% ci , 96%98% ) achieved svr12 ( fig .
table 2 shows svr12 rates in black versus nonblack patients by treatment history , cirrhosis status , regimen , and combined regimen and baseline viral load .
although these subgroups were not powered for formal comparisons , some general observations may be made . among treatmentnave patients without cirrhosis who received 8 weeks of ledipasvir / sofosbuvir with and without ribavirin ,
the rate of svr12 was 90% among blacks versus 94% among nonblacks . in most , but not all , subgroups of those receiving 8 weeks of treatment ,
there are similar differences , with slightly more nonblack patients achieving svr12 than black patients .
the largest difference was between black and nonblack patients with a high viral load at baseline ( hcv rna 6,000,000 ) not receiving ribavirin ( 83% versus 92% ) .
svr12 by baseline factors , treatment history , and regimen patients who did not disclose their race or who were missing cirrhosis status were excluded from the analysis .
abbreviations : ci , confidence interval ; hcv , hepatitis c virus ; ldv , ledipasvir ; rbv , ribavirin ; sof , sofosbuvir ; svr12 , sustained virologic response at 12 weeks after the end of therapy .
overall , 10 black patients ( 3% ) relapsed compared with 26 nonblack patients ( 2% ) , but among patients receiving 8 weeks of treatment , there was a substantial numerical difference : 9% of black patients relapsed versus 4% of nonblack patients . one black patient , a 63yearold man with hcv genotype 1b who was in the 24week ledipasvir / sofosbuvir group of ion1 , had virologic breakthrough at week 8 of treatment .
this patient had undetectable plasma concentrations of ledipasvir and the circulating metabolite of sofosbuvir at weeks 8 and 10 , suggesting nonadherence to the study treatment .
four of these 11 patients had ns5a or ns5b resistanceassociated variants ( ravs ) at baseline , and nine had y93h or q30 ns5a ravs at the time of relapse .
characteristics of black patients with virologic failure abbreviations : f , female ; hcv , hepatitis c virus ; ldv , ledipasvir ; m , male ; pi , protease inhibitor ; rav , resistanceassociated variant ; rbv , ribavirin ; sof , sofosbuvir .
table 4 shows svr12 and virologic failure rates in black and nonblack patients by presence or absence of baseline ns5a ravs .
both black and nonblack patients with baseline ns5a ravs at baseline had rates of svr12 that were numerically lower and rates of virologic failure that were numerically higher than patients without baseline ravs , but the difference was not large ( between 4 and 7 percentage points ) .
black patients with and without ns5a ravs had slightly lower rates of svr12 and higher rates of virologic failure than corresponding groups of nonblack patients , but again the numeric differences were slight ( between 2 and 5 percentage points ) .
virologic outcomes in black and nonblack patients by presence or absence of baseline ns5a ravs for patients for whom sequencing data were available .
differences in response and relapse by race are less evident among patients receiving 12 and 24 weeks of treatment .
overall , rates of svr12 among treatmentnave and treatmentexperienced patients , as well as those with and without cirrhosis , are similarly high in black and nonblack cohorts .
94% for nonblacks , and in patients receiving a 24week regimen , svr12 rates were 100% for nonblacks and 97% for blacks ( table 2 ) .
no racebased differences were evident by cirrhosis status in patients receiving 12 weeks of treatment .
both black and nonblack patients with cirrhosis had an svr12 rate of 92% , which was lower than the rate in patients without cirrhosis , but black and nonblack patients without cirrhosis had similar rates of svr12 ( 99% versus 97% ) . in patients receiving 24 weeks of treatment , however , a lower proportion of black patients with cirrhosis had svr12 ( 90% ) than nonblack patients with cirrhosis ( 100% ) , however , there were only 10 black patients with cirrhosis in this group .
the efficacy of ledipasvir / sofosbuvir did not appear to be greatly affected by the presence of ribavirin in black or nonblack patients .
the four analysis groups of patients receiving 12 weeks of treatment  black patients receiving ribavirin , black patients not receiving ribavirin , nonblack patients receiving ribavirin , and nonblack patients not receiving ribavirin  all had very similar svr12 rates within the range of 96%99% . among patients receiving 24 weeks of treatment , one group 
black patients not receiving ribavirin  had an svr12 rate that was substantially lower ( 92% ) than that of the other groups ( 99%100% ) . for a safety analysis , we pooled patients by race ( black versus nonblack ) and drug combination ( ledipasvir / sofosbuvir versus ledipasvir / sofosbuvir plus ribavirin ) .
the most common adverse events in all groups were fatigue , headache , nausea , and insomnia ( table 5 ) . dose modification or interruption
was required in 13% of black patients and 14% of nonblack patients receiving ledipasvir / sofosbuvir plus ribavirin compared with < 1% of black and nonblack patients receiving ledipasvir / sofosbuvir alone . in general , a numerically larger percentage of black patients receiving ledipasvir / sofosbuvir plus ribavirin had safety events than black patients receiving ledipasvir / sofosbuvir alone .
the same was true for nonblack patients ; more nonblack patients receiving ledipasvir / sofosbuvir plus ribavirin experienced safety events than those receiving ledipasvir / sofosbuvir alone .
overall safety by race events occurring in at least 10% of patients in any treatment group .
of the 1952 patients randomized and treated in the ion studies , 308 ( 16% ) selfreported their race as black .
of the remaining 1644 patients in these studies , three declined to report race , leaving 1641 nonblack patients for comparison in this analysis .
overall , approximately one quarter of the patients had a bmi 30 kg / m ; this proportion was considerably higher among black patients than it was among nonblack patients ( 41% versus 23% ) .
overall , 12% of patients , but only 7% of blacks , had compensated cirrhosis . as expected , more blacks had noncc il28b genotypes than nonblacks ( 90% versus 73% ) . the mean alanine aminotransferase level for blacks ( 61
u / l ) was lower than that of nonblacks ( 77 u / l ) . among the ion study participants ,
similar proportions of black and nonblack patients were treatmentexperienced and had hcv rna 800,000 iu / ml . abbreviations : alt , alanine aminotransferase ; bmi , body mass index ; egfr , estimated glomerular filtration rate ; hcv , hepatitis c virus .
overall , 95% of black patients ( 95% confidence interval [ ci ] , 92%97% ) and 97% of nonblack patients ( 95% ci , 96%98% ) achieved svr12 ( fig .
table 2 shows svr12 rates in black versus nonblack patients by treatment history , cirrhosis status , regimen , and combined regimen and baseline viral load .
although these subgroups were not powered for formal comparisons , some general observations may be made . among treatmentnave patients without cirrhosis who received 8 weeks of ledipasvir / sofosbuvir with and without ribavirin ,
in most , but not all , subgroups of those receiving 8 weeks of treatment , there are similar differences , with slightly more nonblack patients achieving svr12 than black patients .
the largest difference was between black and nonblack patients with a high viral load at baseline ( hcv rna 6,000,000 ) not receiving ribavirin ( 83% versus 92% ) .
svr12 by baseline factors , treatment history , and regimen patients who did not disclose their race or who were missing cirrhosis status were excluded from the analysis .
abbreviations : ci , confidence interval ; hcv , hepatitis c virus ; ldv , ledipasvir ; rbv , ribavirin ; sof , sofosbuvir ; svr12 , sustained virologic response at 12 weeks after the end of therapy .
overall , 10 black patients ( 3% ) relapsed compared with 26 nonblack patients ( 2% ) , but among patients receiving 8 weeks of treatment , there was a substantial numerical difference : 9% of black patients relapsed versus 4% of nonblack patients .
one black patient , a 63yearold man with hcv genotype 1b who was in the 24week ledipasvir / sofosbuvir group of ion1 , had virologic breakthrough at week 8 of treatment .
this patient had undetectable plasma concentrations of ledipasvir and the circulating metabolite of sofosbuvir at weeks 8 and 10 , suggesting nonadherence to the study treatment .
four of these 11 patients had ns5a or ns5b resistanceassociated variants ( ravs ) at baseline , and nine had y93h or q30 ns5a ravs at the time of relapse .
characteristics of black patients with virologic failure abbreviations : f , female ; hcv , hepatitis c virus ; ldv , ledipasvir ; m , male ; pi , protease inhibitor ; rav , resistanceassociated variant ; rbv , ribavirin ; sof , sofosbuvir . table 4 shows svr12 and virologic failure rates in black and nonblack patients by presence or absence of baseline ns5a ravs .
both black and nonblack patients with baseline ns5a ravs at baseline had rates of svr12 that were numerically lower and rates of virologic failure that were numerically higher than patients without baseline ravs , but the difference was not large ( between 4 and 7 percentage points ) .
black patients with and without ns5a ravs had slightly lower rates of svr12 and higher rates of virologic failure than corresponding groups of nonblack patients , but again the numeric differences were slight ( between 2 and 5 percentage points ) .
virologic outcomes in black and nonblack patients by presence or absence of baseline ns5a ravs for patients for whom sequencing data were available .
differences in response and relapse by race are less evident among patients receiving 12 and 24 weeks of treatment .
overall , rates of svr12 among treatmentnave and treatmentexperienced patients , as well as those with and without cirrhosis , are similarly high in black and nonblack cohorts .
94% for nonblacks , and in patients receiving a 24week regimen , svr12 rates were 100% for nonblacks and
, no racebased differences were evident by cirrhosis status in patients receiving 12 weeks of treatment .
both black and nonblack patients with cirrhosis had an svr12 rate of 92% , which was lower than the rate in patients without cirrhosis , but black and nonblack patients without cirrhosis had similar rates of svr12 ( 99% versus 97% ) . in patients receiving 24 weeks of treatment ,
however , a lower proportion of black patients with cirrhosis had svr12 ( 90% ) than nonblack patients with cirrhosis ( 100% ) , however , there were only 10 black patients with cirrhosis in this group .
the efficacy of ledipasvir / sofosbuvir did not appear to be greatly affected by the presence of ribavirin in black or nonblack patients .
the four analysis groups of patients receiving 12 weeks of treatment  black patients receiving ribavirin , black patients not receiving ribavirin , nonblack patients receiving ribavirin , and nonblack patients not receiving ribavirin  all had very similar svr12 rates within the range of 96%99% . among patients receiving 24 weeks of treatment , one group 
black patients not receiving ribavirin  had an svr12 rate that was substantially lower ( 92% ) than that of the other groups ( 99%100% ) .
for a safety analysis , we pooled patients by race ( black versus nonblack ) and drug combination ( ledipasvir / sofosbuvir versus ledipasvir / sofosbuvir plus ribavirin ) .
the most common adverse events in all groups were fatigue , headache , nausea , and insomnia ( table 5 ) .
dose modification or interruption was required in 13% of black patients and 14% of nonblack patients receiving ledipasvir / sofosbuvir plus ribavirin compared with < 1% of black and nonblack patients receiving ledipasvir / sofosbuvir alone . in general , a numerically larger percentage of black patients receiving ledipasvir / sofosbuvir plus ribavirin had safety events than black patients receiving ledipasvir / sofosbuvir alone .
the same was true for nonblack patients ; more nonblack patients receiving ledipasvir / sofosbuvir plus ribavirin experienced safety events than those receiving ledipasvir / sofosbuvir alone . for both dose combinations , fewer black patients than nonblack patients had safety events .
overall safety by race events occurring in at least 10% of patients in any treatment group .
in this analysis of data from the ion phase 3 clinical trials evaluating the fixeddose combination of ledipasvir / sofosbuvir with and without ribavirin in treatmentnave and previously treated patients with genotype 1 hcv , we found that black patients had rates of svr12 similar to those in nonblack patients , regardless of treatment history , treatment duration , or cirrhosis status . among the 308 patients who selfidentified as black , svr12 rates were high ( 90% ) even among those with compensated cirrhosis and those who had previously failed previous treatment , including treatment with a protease inhibitor and peginterferon / ribavirin .
the addition of ribavirin did not appear to increase svr12 rates but led to higher rates of adverse events .
the factor that appeared to be most strongly associated with response was treatment duration ; the rate of relapse among black patients in the 8week treatment arms of ion3 was 8.6% compared with 1.5% among blacks receiving 12 weeks of treatment and 1.1% among blacks receiving 24 weeks of treatment .
even so , this result likely understates the difference in response by treatment duration , given that the 8week group enrolled only treatmentnave patients without cirrhosis , whereas the groups receiving 12 and 24 weeks of treatment included previously treated patients and those with cirrhosis .
if patients receiving the clearly suboptimal duration of 8 weeks are omitted from the analysis , there are not enough patients with virologic failure ( n  =  3 ) to make any generalizations concerning factors predictive of treatment success or failure . given the known safety profile of ribavirin
, higher rates of adverse events in patients receiving ribavirin than in those receiving sofosbuvirledipasvir alone were expected .
this pattern was evident in comparing black patients who did and did not receive ribavirin and nonblack patients who did and did not receive ribavirin .
what was unexpected was that black patients receiving ledipasvir / sofosbuvir and those receiving ledipasvir / sofosbuvir plus ribavirin had consistently lower rates of most adverse events than nonblack patients ( table 4 ) .
the reason for these differences is not known but may be partly explained by the fact that a slightly higher percentage of black patients than nonblack patients received 8 weeks of treatment ( 26% versus 21% ) and a lower percentage of black patients had cirrhosis ( 7% versus 12% ) .
one might have expected , however , that these differences would have been offset by the higher mean age and bmi among black patients .
our analysis is limited by the retrospective framework and need to combine the black population across all three of the ion studies for these comparisons .
overall , the ion1 , 2 , and 3 studies achieved a relatively good level of diversity with black patients representing 16% of the study population .
however , even with 300 patients , we lose the necessary means to achieve reliable results when attempting to look at subgroups , such as when examining compensated cirrhosis in blacks ( only 38 patients ) . therefore , although the ion1 , 2 , and 3 studies when combined achieved a relatively diverse population for analysis , the overall population was still too small to perform the nuanced analyses required to definitively show efficacy and safety in diverse populations .
a lack of participation of minorities in clinical trials is a major barrier to identifying treatment regimens for diverse populations .
blacks are disproportionally affected by hcv and represent the majority of patients treated for hcv within certain communities across the united states , yet they are severely underrepresented in hcv clinical trials . given the known historical differences in svr based on race , the black population within clinical trials must be increased .
a recent report of data from the ion4 study looking at the fixeddose combination of ledipasvir and sofosbuvir for treating hcv in coinfected patients highlights the need for these types of analyses.15 here , among individuals coinfected with hcv and hiv , the overall svr12 rate was 96% .
similar svr rates were achieved for treatmentnave and treatmentexperienced participants ( 95% and 97% , respectively ) , and for subjects with and without cirrhosis ( 94% and 96% , respectively).15 however , black patients had lower svr12 rates than nonblack patients ( 90% [ 95% ci , 83%95% ] versus 99% [ 95% ci , 97%100% ] ; p < 0.001 ) .
all 10 patients who experienced virologic relapse in this trial were black . in a multivariate analysis ,
population pharmacokinetics of ledipasvir was the same when comparing black versus nonblack race , efavirenz versus nonefavirenz antiretroviral regimens , and svr versus relapse .
this is the first study of directacting antivirals to suggest a lower svr in black patients .
this finding needs to be confirmed in other studies , which will only be achieved if future trials are powered with respect to population diversity to address this question.15 
  this is an exciting time in the treatment of viral hepatitis .
we are now identifying alloral , well tolerated , safe , and efficacious treatments for hcv .
future work within this field of hepatology will need to ensure that these regimens are safe and efficacious in all populations affected by hcv .
the ion4 study is an example of the kind of potentially surprising results that can be obtained when a clinical trial includes an appropriate population of underrepresented minorities .
whether the ion4 findings are an aberration , unique to that trial , or strictly relevant to coinfected populations is unclear ; only further studies of diverse populations can settle these questions .
here , we show that an all oral interferonfree regimen has great potential because of its equal efficacy and safety in an underrepresented population . due to the relatively small population ,
however , it is important that future studies confirm these findings using study populations that have a larger minority population .
 black patients chronically infected with genotype 1 hepatitis c virus ( hcv ) have historically had lower rates of response to interferonbased treatment than patients of other races . in the phase 3 ion program , 
 the singletablet regimen of the ns5a inhibitor ledipasvir and ns5b nucleotide polymerase inhibitor sofosbuvir was shown to be safe and highly effective in the general population . 
 the aim of this study was to evaluate the safety and efficacy of ledipasvir / sofosbuvir in black patients using data from the three openlabel ion clinical trials , which evaluated the safety and efficacy of 8 , 12 , and 24 weeks of ledipasvir / sofosbuvir with or without ribavirin for the treatment of treatmentnave and treatmentexperienced patients with genotype 1 hcv , including those with compensated cirrhosis . 
 the primary endpoint was sustained virologic response at 12 weeks after the end of therapy ( svr12 ) . for our analysis 
 , rates of svr12 , treatmentemergent adverse events , and graded laboratory abnormalities were analyzed in black versus nonblack patients . of the 1949 patients evaluated , 
 308 ( 16% ) were black . on average , black patients were older , had higher body mass index , were more likely to be il28b noncc , and had a lower serum alanine aminotransferase at baseline than nonblack patients . 
 overall , 95% of black and 97% of nonblack patients achieved svr12 . 
 the rate of relapse was 3% in black patients as compared with 2% in nonblack patients . 
 the most common adverse events included fatigue , headache , nausea , and insomnia . 
 the majority of adverse events occurred more frequently in the ribavirincontaining arms of the studies . 
 no differences were observed in overall safety by race . 
 conclusion : a oncedaily dosage of ledipasvir / sofosbuvir was similarly effective in black and nonblack patients with genotype 1 hcv infection . 
 the addition of ribavirin did not appear to increase svr12 but was associated with higher rates of adverse events . 
 ( hepatology 2016;63:437444 ) 
Patients and Methods
Results
Demographics
Efficacy
Safety
Discussion